Palladium-catalyzed regioselective ortho-acetoxylation of 3-aryl-1,2,4-benzotriazines via C-H activation

Article abstract of DOI:10.1055/s-0033-1338702

A highly regioselective ortho-acetoxylation has been achieved in the presence of 10 mol% Pd(OAc)₂ and a stoichiometric amount of PhI(OAc)₂ in a mixture of acetic anhydride and acetic acid via C-H activation to produce the corresponding acetoxy-substituted 3-aryl-1,2,4- benzotriazines derivatives in good yields. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1338702

LETTER
▌1395
letter
Palladium-Catalyzed Regioselective ortho-Acetoxylation of 3-Aryl-1,2,4-
Benzotriazines via C–H Activation
ortho-Acetoxylation of 3-Aryl-1,2,4-Benzotriazines
Xiaoyu Ren,a,b Jin Liu,a,b,c Hao Yan,a,b Xiaokang Shi,a,b Sizhuo Yang,a,b Jian Li,a,b Guosheng Huang*a,b
a
State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, P. R. of China
Fax +86(931)8912582; E-mail: hgs@lzu.edu.cn
b
Key Laboratory of Nonferrous Metal Chemistry and Resources Utilization of Gansu Province, Lanzhou 730000, P. R. of China
c
Institute of Chemical Engineering, Hubei Sanonda Co., Ltd. , No. 93, East Beijing RD., Jingzhou, Hubei 434001, P. R. of China
Received: 04.03.2013; Accepted after revision: 11.04.2013
(2a) was obtained in 45% yield after six hours. Among the
Pd sources we examined, Pd(OAc)2 showed the highest
activity for this reaction (Table 1, entries 2–4). Then sev-
eral other oxidants were evaluated, and the results showed
that PhI(OAc)2 was superior to Oxone, K2S2O8, 1,4-ben-
zoquinone (BQ), and Cu(OAc)2 (Table 1, entries 5–8).
Thus, PhI(OAc)2 was chosen as the oxidant for further op-
timization. Moreover, we have performed the reaction in
various solvents. The reaction was sluggish either in
MeCN or in Ac2O (Table 1, entries 9 and 13). The use of
1,2-dichloroethane (DCE), toluene, and AcOH did not im-
prove the yield of the product relative to AcOH–Ac2O
(Table 1, entries 10–12). Furthermore, changing the ratio
of AcOH vs. Ac2O did not improve the yield (Table 1, en-
tries 14 and 15). Other than oxidant and solvent, the reac-
tion temperature and time were also crucial for the
reaction, the yield of 2a decreased at both higher and low-
er temperature than 100 °C (Table 1, entry 16: 80 °C, en-
try 17: 120 °C); and the yield also decreased at longer and
shorter reaction time than six hours (Table 1, entries 18: 4
h, 19: 8 h). Therefore, the optimized conditions were iden-
tified (Table 1, entry 4).
Abstract: A highly regioselective ortho-acetoxylation has been
achieved in the presence of 10 mol% Pd(OAc)2 and a stoichiometric
amount of PhI(OAc)2 in a mixture of acetic anhydride and acetic
acid via C–H activation to produce the corresponding acetoxy-sub-
stituted 3-aryl-1,2,4-benzotriazines derivatives in good yields.
Key words: palladium catalyst, acetoxylation, C–H activation,
3-aryl-1,2,4-benzotriazines
The direct conversion of C–H bonds into C–O, C–N,
C–S, C–halogen, and C–C bonds has been actively inves-
tigated in organic synthesis.1 Great efforts have been de-
voted to the development of efficient methods for the
direct C–H bond functionalization because of their poten-
tial in forming diverse derivatives.2 Transition-metal
complexes have been widely used as catalysts in C–H
bond activation, and palladium catalysts are particularly
attractive. Generally, the directing group possesses a lone-
pair electron and coordinates the transition-metal catalyst
via a five- or six-membered metallacycle to direct an
ortho functionalization.3 In recent years, the development
of regioselective C–O bond formation via C–H activation
received significant attention of organic chemists.4
Table 1 Optimization of the Reaction Conditionsa
1,2,4-Benzotriazine contains three nitrogen atoms and be-
longs to a special class of aromatic heterocycles, it is usu-
ally considered more significant than simple pyridine and
quinoline rings.5 It has been involved in many compounds
and reactions such as aza nucleosides and aza nucleo-
tides,6 ligands,7 herero Diels–Alder reactants,8 herbicid-
al,9 and metal-ion adsorption,10 and it has been found in
various agrochemicals, functional materials, and biologi-
cally active compounds.11 Moreover, as a directing group,
1,2,4-benzotriazine is a useful building block for its po-
tentially bioactive phenyl derivatives. Herein, we report a
suitable and efficient method for the C–O bond formation
on a phenyl ring via 1,2,4-benzotriazine-directed C–H
activation with palladium catalysts.
N
N
N
N
N
catalyst, oxidant
solvent
N
AcO
Entry Catalyst
Oxidant
Solvent
Time Yield
(h)
(%)
1
2
3
4
5
6
7
8
PdCl2
PhI(OAc)2
PhI(OAc)2
AcOH–Ac2O 6
45b
28b
39b
72b
42b
51b
n.d.b
n.d.b
trace
53
Pd(Ph3P)2Cl2
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
PdCl2C4H6N2 PhI(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PhI(OAc)2
Oxone
Initially, we examined the reaction of 3-aryl-1,2,4-benzo-
triazine (1a) with PhI(OAc)2 in AcOH–Ac2O (1:1) cata-
lyzed by PdCl2 at 100 °C (Table 1, entry 1). Gratifyingly,
the desired 2-{benzo[e][1,2,4]triazin-3-yl}phenyl acetate
K2S2O8
BQ
Cu(OAc)2
PhI(OAc)2
PhI(OAc)2
SYNLETT 2013, 24, 1395–1398
Advanced online publication: 08.05.2013
9
MeCN
DCE
6
6
0
9
3
6
-
5
2
1
4
1
4
3
7
-
2
0
9
6
DOI: 10.1055/s-0033-1338702; Art ID: ST-2013-W0189-L
© Georg Thieme Verlag Stuttgart · New York
10

1396
X. Ren et al.
LETTER
Table 1 Optimization of the Reaction Conditionsa (continued)
product was not isolated, and only a trace amount of the
product was detected on silica gel (Table 2, entry 8). Fur-
thermore, for substitution on the 1,2,4-benzotriazine,
electron-donating substituted compounds (Table 2, entry
10: 70%, entry 11: 63%) gave slightly higher yields than
those with electron-withdrawing substituents (Table 2,
entry 12: 62%), but dimethyl substitution did not give bet-
ter yield than single methyl substitution. For compounds
with substitution at both phenyl and aryl rings, electron-
rich 3-aryl-1,2,4-benzotriazines showed better reactivity
and achieved higher yields than electron-deficient ones
(Table 2, entries 13–17). Notably, 3-fury-1,2,4-benzotri-
azines can also undergo this transformation, albeit in 14%
yield (Scheme 2, 2q).
N
N
N
N
N
N
catalyst, oxidant
solvent
AcO
Entry Catalyst
Oxidant
Solvent
Time Yield
(h)
(%)
11
12
13
14
15
16
17
18
19
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
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
PhI(OAc)2
toluene
AcOH
Ac2O
6
6
6
47
34
11
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 6
AcOH–Ac2O 4
AcOH–Ac2O 8
38c
23d
53b,e
48b,f
43b
59b
N
N
N
N
OAc
N
N
Pd(OAc)2 (10% mol)
PhI(OAc)2 (2.2 equiv)
AcOH–Ac2O, 100 °C, 6 h
AcO
3a
Scheme 1 Synthesis of 2-{benzo[e][1,2,4]triazin-3-yl}-1,3-phenyl-
ene diacetate from 3-aryl-1,2,4-benzotriazine
a Reaction conditions: The reaction was carried out using 1a (0.2
mmol), catalyst (0.02 mmol), and oxidant (0.22 mmol) in solvent (1
mL) under air for 6 h at 100 °C.
N
N
b Yield for AcOH–Ac2O (1:1).
N
Pd(OAc)2 (10% mol)
PhI(OAc)2 (1.1 equiv)
N
c Yield for AcOH–Ac2O (2:1).
O
O
d Yield for AcOH–Ac2O (1:2).
N
N
AcOH–Ac2O, 100 °C, 6 h
e Yield for a reaction temperature of 80 °C.
f Yield for a reaction temperature of 120 °C.
AcO
2q
Scheme 2 Synthesis of 2-{benzo[e][1,2,4]triazin-3-yl}furan-3-yl
acetate from 3-fury-1,2,4-benzotriazine
3-Aryl-1,2,4-benzotriazine presents two ortho C–H bonds
that can coordinate with Pd at both 2,6-positions, but with
1.1 equivalents of PhI(OAc)2 the monosubstituted product
was obtained in good yield (Table 2, entry 1). When in-
crease the feed of PhI(OAc)2 to 2.2 equivalents, only the
disubstituted product was detected (Scheme 1, 3a). Using
the optimized conditions, we also examined a series of 3-
aryl-1,2,4-benzotriazine compounds to establish the scope
and limitations of this process. Generally, the reaction of
3-aryl-1,2,4-benzotriazine bearing either electron-with-
drawing or electron-donating groups proceeded smoothly
and afforded the corresponding desired product 2 in mod-
erate to good yields (Table 2). However, the compounds
with electron-donating functional groups on the aryl ring
(Table 2, entries 1–4) generally gave higher yields than
those with electron-withdrawing groups (Table 2, entries
5 and 6; 72–84% for 2a–d vs. 58–60% for 2e–f). Interest-
ingly, methyl groups on the aryl ring seem to facilitate the
reaction (Table 2, entries 2–4), and the 4-methyl-substi-
tuted compound gave the highest yield (Table 2, entry 2:
84%). However, the stronger electron-donating methoxy
group on the aryl ring gave the product in low yield (Table
2, entry 7). To our surprise, the compound with the strong
electron-withdrawing nitro group at the meta position
gave the product in 31% yield (Table 2, entry 9). How-
ever, the compound with the nitro group at the para posi-
tion may not be suitable for the process as the desired
N
N
N
N
N
N
AcO
PdII
OAc
HOAc
N
N
N
N
N
AcO
N
PdIV
OAc
PdII
(1)
(a)
PhI(OAc)2
(b)
AcOH
Scheme 3 Proposed reaction mechanism
Synlett 2013, 24, 1395–1398
© Georg Thieme Verlag Stuttgart · New York

LETTER
ortho-Acetoxylation of 3-Aryl-1,2,4-Benzotriazines
1397
Table 2 Substrate Scope of 3-Aryl-1,2,4-benzotriazinesa
N
N
N
Pd(OAc)2 (10% mol)
PhI(OAc)2 (1.1 equiv)
N
R1
R1
N
N
R2
R2
AcOH–Ac2O, 100 °C, 6 h
AcO
Entry
R1
R2
Product
Yield (%)
1
2
H
H
2a
2b
2c
2d
2e
2f
72
84
82
78
60
58
36
trace
31
70
63
62
73
64
65
56
53
H
4-Me
3-Me
3,5-Me2
4-Cl
3-Cl
4-MeO
4-O2N
3-O2N
H
3
H
4
H
5
H
6
H
7
H
2g
8
H
9
H
2h
2i
10
11
12
13
14
15
16
17
4-Me
4,5-Me2
4-Cl
4,5-Me2
4-Cl
4-Me
4-Me
4,5-Me2
H
2j
H
2k
2l
4-Me
4-Me
4-Cl
3-Cl
4-Cl
2m
2n
2o
2p
a Reaction conditions: The reaction was carried out using 1a (0.2 mmol), Pd(OAc)2 (0.02 mmol), and PhI(OAc)2 (0.22 mmol) in AcOH–
Ac2O (1 mL) under air for 6 h at 100 °C.
A plausible reaction mechanism based on the results ob- ly in moderate to good yields. Additionally, the approach
tained above combined with previous reports12 has been provides a new access to a variety of acetoxy-susbstituted
proposed in Scheme 3. We assume that the reaction may 3-aryl-1,2,4-benzotriazines derivatives which may be im-
undergo according to the following procedures. 1,2,4-Tri- portant in medicinal chemistry for drug discovery and de-
azine-directed C–H activation generates a five-membered velopment. The application of 1,2,4-benzotriazines as a
cyclopalladated intermediate,13 the intermedium pallada- directing group to construct carbon–heteroatom bonds,
cycle is stabilized with the 1,2,4-triazine group to induce and other further investigations, are under way in our lab-
the ortho acetoxylation.14 The resulting PdII could be con- oratory.
verted into PdIV by PhI(OAc)2 to complete the catalytic
cycle (Scheme 3, a).15 An alternative peroxide-based oxi-
Acknowledgment
dant may also give the key PdIV intermediate 1 when em-
The authors thank the State Key Laboratory of Applied Organic
Chemistry for financial support.
ploying an external acetate source such as acetic acid
(Scheme 3, b).16
In conclusion, we have developed a direct palladium-cat-
alyzed method for the synthesis of 2-{benzo[e][1,2,4]tri-
azin-3-yl}phenyl acetate derivatives form 3-aryl-1,2,4-
benzotriazines using 10 mol% Pd(OAc)2 and with
PhI(OAc)2 as oxidation agent in AcOH–Ac2O in air in a
one-pot manner, involving the cleavage of a C–H bond
and the formation of a C–O bond. A variety of substitu-
ents are tolerated in this reaction, which proceeds smooth-
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© Georg Thieme Verlag Stuttgart · New York
Synlett 2013, 24, 1395–1398

1398
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LETTER
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A test tube was charged with 1a (0.2 mmol), Pd(OAc)2 (0.02
mmol), and PhI(OAc)2 (0.22 mmol). Then AcOH–Ac2O (1
mL) was added to the reaction system. The reaction was
stirred at 100 °C under air for 6 h. After cooling to r.t., the
solvent was diluted with EtOAc (10 mL) and washed with
brine (5 mL) and dried over anhyd Na2SO4. After the solvent
was evaporated in vacuo, the residues were purified by
column chromatography, eluting with PE–EtOAc to afford
38 mg (72%) pure 2a as yellow solid, mp 102–105 °C. 1H
NMR (400 MHz, CDCl3): δ = 8.55 (d d, J = 8.0 Hz, 1.6 Hz,
2 H), 8.07–8.05 (m, 1 H), 8.01–7.97 (m, 1 H), 7.89–7.85 (m,
1 H), 7.62–7.58 (m, 1 H), 7.51–7.47 (m, 1 H), 7.27 (d d,
J = 8.0 Hz, J = 1.6 Hz, 1 H), 2.39 (s, 3 H). 13C NMR (100
MHz, CDCl3): δ = 169.9, 159.3, 149.7, 145.8, 140.6, 135.6,
132.1, 132.1, 130.6, 129.5, 128.9, 128.6, 126.5, 124.2, 21.2.
IR (neat): 3070, 2924, 2853, 1768, 1514, 1458, 1372, 1322,
1198, 1100, 1012, 769 cm–1. ESI-HRMS: m/z calcd for
C15H11N3O2 [M + H]+: 266.0930; found: 266.0922.
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Synlett 2013, 24, 1395–1398
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