One-Pot Protocol to Synthesize 2-Aminophenols from Anilines via Palladium-Catalyzed C-H Acetoxylation

Article abstract of DOI:10.1021/acs.organomet.9b00113

This paper describes a facile one-pot protocol to synthesize 2-aminophenol derivatives via a palladium-catalyzed C-H acetoxylation strategy with 5-nitropyrimidine as a directing group (DG), which can be easily preinstalled and readily removed under mild condition after the coupling. In addition, the transformation is operationally simple, has high functional group tolerance, and is amenable to gram-scale. Moreover, several examples were shown that introduction/removal of 5-nitropyrimidine and the C-H oxylation sequence could be integrated in one pot.

Full text of DOI:10.1021/acs.organomet.9b00113

Article
pubs.acs.org/Organometallics
Cite This: Organometallics XXXX, XXX, XXX−XXX
One-Pot Protocol To Synthesize 2‑Aminophenols from Anilines via
Palladium-Catalyzed C−H Acetoxylation
Junhao Zhao,# Yifeng Huang,# Guojian Ma, Ling Lin, and Pengju Feng*
Department of Chemistry, Jinan University, Guangzhou 510632, China
S
* Supporting Information
ABSTRACT: This paper describes a facile one-pot protocol to synthesize 2-aminophenol derivatives via a palladium-catalyzed
C−H acetoxylation strategy with 5-nitropyrimidine as a directing group (DG), which can be easily preinstalled and readily
removed under mild condition after the coupling. In addition, the transformation is operationally simple, has high functional
group tolerance, and is amenable to gram-scale. Moreover, several examples were shown that introduction/removal of 5-
nitropyrimidine and the C−H oxylation sequence could be integrated in one pot.
INTRODUCTION
■
In recent years, with the rise of transition-metal-catalyzed C−
H bond activation, directing group (DG) assisted Csp2−H
bond functionalization has attracted wide attention.1−14
Various directing groups, such as amine,15 imine,16 oxime,17
diazene,18 amide,19−24 carboxylic acid,25 among others,26−29
were exploited to achieve regioselective C−H functionaliza-
tion. The pyrimidyl and pyridyl moieties, strongly coordinated
DGs, which easily formed a thermodynamically stable five- or
six-membered metallacycle with the transition metal for
facilitating the C−H activation step, have been more actively
studied.30−37 The inevitable major problems associated with
pyrimidyl/pyridyl-directed C−H functionalization are separate
step to introduce them and harsh condition to remove
them.38−41 Notably, ortho-functionalization of 2-phenoxypri-
dines and 2-phenoxypyrimidines have been extensively
reported, while similar transformations were seldom able to
Figure 1. C(sp2)−H functionalization of phenol and aniline
apply to aniline derivatives because the free amino group could
facilitate other side reactions.42−51
derivatives with directing groups.
Pyrimidyl/pyridyl assisted ortho-oxylation phenols with an
alization for sustainable synthesis, we present here a syntheti-
easily accessible palladium catalyst have been well estab-
lished.33,42,52−54 The developed catalytic system could be
extended to various aniline derivatives after certain mod-
ification, such as protected phenylamide,55−58 phenylnitrous
amide,59,60 and phenyldiazene61,62 (Figure 1), while these
reactions often suffer limited substrate group and difficult-to-
remove directing group. Structurally versatile pyrimidyl/
pyridyl anilines are not capable for these transformations
thus far. We questioned whether it might be possible to expand
application of palladium-catalyzed oxylation to anilines masked
by functional pyrimidyl/pyridyl group, proving a short cut to
aminophenols which are key structural motifs of numerous
bioactive compounds used in crop protection and medicinal
chemistry.63−67 To provide more practicable C−H function-
cally convenient Pd-catalyzed C−H acetoxylation reaction for
aniline/phenol substrates with easy-to-handle directing groups
(Figure 1). Our method enables the direct preparation of
ortho-oxylation-free anilines. Notable features of our general
strategy include (1) structurally diversified aniline derivatives
can be successfully ortho-acetoxylated under one-pot reaction
condition; (2) both the C−H functionalization and the mild
directing group removal procedure have high function group
tolerance; and (3) the transformation from aniline derivatives
to 2-aminophenol derivatives is amenable to a gram-scale
Received: February 19, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.organomet.9b00113
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Article
synthesis and the practical auxiliary, 5-nitropyrimidine, was
successfully applied as a transient directing group during
introduction of DG, C−H functionalization and removal of
DG.
derivatives to be further protected by Ac2O and oxidized by
PhI(OAc)2.68−70 Moreover, 5-nitropyrimidine could work as a
DG to promote ortho-acetoxylation of aniline.
The reaction optimization was outset by using aniline 1a as
model substrate which was mixed with 2-chloro-5-nitro-
pyrimidine to give the intermediate compound 1a′ for the
directly usage of next step. After the addition of HOAc (0.2 M
1a), Pd(OAc)2 (10 mol %), PhI(OAc)2 (1.5 equiv), the
reaction was stirred for 12 h.72−75 Subsequent workup
furnished the ortho-acetoxylation product 2a in 35% yield
(Table 1, entry 1). Encouraged by this, various solvents,
oxidants, and metal catalysts were screened to get the optimal
yield of the product 2a. Among the solvents screened, a mixed
solvent system (HOAc/Ac2O = 1:1) turned out to be the most
effective choice to deliver product in 60% yield (Table 1,
entries 2−6). The oxidant PhI(OAc)2 was crucial for the
acetoxylation. Its absence or the replacement with another
oxidant, such as K2S2O8, benzoxyl peroxide, H2O2, or O2,
would not result in any significant amount of product (Table 1,
entries 7−11). The amount of PhI(OAc)2 directly affected the
efficiency of the reaction, and 1.1 equiv of PhI(OAc)2 gave the
best yield and only a monofunctionalization product was
observed (Table 1, entries 12, 13). Gratifyingly, a better yield
was obtained in a much shorter reaction time (Table 1, entries
14, 15). Palladium acetate was superior to other tested metal-
catalysts, including [RhCp*Cl2]2 and RuCl2(p-cymene) (Table
1, entries 16−18) for this transformation.
RESULTS AND DISCUSSION
■
There is much difference between DG-assisted functionaliza-
tion of anilines and phenols, especially involving oxidant
during the transformation. Preprotection of anilines is usually
employed to avoid the nitrogen being oxidized or acting as a
reactive site to participate further transformation.59,68−71 In
our initial study, the coupling reaction between different
pyrimidyl/pyridyl- derivatives and aniline, along with further
potential DG assisted ortho-acetoxylated were invested
(Scheme 1). The results turned out to be that 5-nitro-
Scheme 1. Reactivity of Different DGs
With the optimized condition in hand, the versatility of C−
H acetoxylation of aniline derivatives was carefully explored
(Table 2). Electron-rich aniline derivatives with or without
ortho- and meta-substituted groups did not show much
difference and gave the desired products 2a−2d in 63%−75%
pyrimidine, unlike pyridine and pyrimidine units, was the
easiest to be introduced, which could avoid aniline
Table 1. Optimization of the One-Pot Procedure
b
c
entry
catalyst
oxidant
solvent
time (h)
yield
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
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
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
−
Phl(OAc)2 (1.5 equiv)
Phl(OAc)2 (1.5 equiv)
Phl(OAc)2 (1.5 equiv)
Phl(OAc)2 (1.5 equiv)
Phl(OAc)2 (1.5 equiv)
Phl(OAc)2 (1.5 equiv)
−
K2S2O8 (1.1 equiv)
benzoxyl peroxide
H2O2 (1.1 equiv)
O2(buloom)
Phl(OAc)2 (0.5 equiv)
Phl(OAc)2 (1.1 equiv)
Phl(OAc)2 (1.1 equiv)
Phl(OAc)2 (1.1 equiv)
Phl(OAc)2 (1.1 equiv)
Cu(OAc)2 (2.2 equiv)
Phl(OAc)2 (1.1 equiv)
HOAc
Ac2O
12
12
12
12
12
12
12
12
12
12
12
12
12
6
35%
trace
10%
39%
29%
HOAc:MeCN = 1.1
HOAc:Ac2O = 3.1
HOAc:Ac2O = 1.3
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
HOAc:Ac2O = 1.1
d
58%
0
trace
trace
trace
trace
35%
68%
75%
56%
0
4
6
6
6
[RhCp*Cl2]2
RuCl2(p-cymene)
trace
trace
a
b
All reactions were run on a 0.5 mmol scale of 1a with its concentration of 0.2 M at 100 °C. The loading of catalyst was tested, and the yield of
product is similar when 5 mol % or 10 mol % of Pd(OAc)2 was used. A lower yield was obtained when we only use 2 mol % of the catalyst.
c
d
Isolated yield. bis-C-H acetoxylation product was detected by LC-MS.
B
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which readily delivered the desired product with less steric
hindrance in moderate yields (2r, 58%, 2s, 51%, 2t, 62%, 2x,
33%).
Table 2. Substrate Scope of Pd-Catalyzed C−H
Acetoxylation of Aniline Derivatives
To demonstrate both the practicality and effectiveness of our
method, compound 2g with a bromo group for further
transformation was prepared on a gram scale under the
standard condition in the slightly longer time (Scheme 2a).
Scheme 2. Further Investigation of This Transformation
Both the directing group (2-N- and -O- 5-nitropyrimidine) and
the acyl group can be cleaved by hydrazine monohydrate in
THF at room temperature or ammonium hydroxide in
methanol at 50 or 60 °C if safer handling is required (Scheme
2b). Moreover, the two-step ortho-acetoxylation and removal
of the directing group sequence in one pot was carried out to
give compound 2f′, 2g′, 2h′ in 61%, 52%, 52% yield,
respectively (Scheme 2c).
a
The reactions were run on a 1.0 mmol scale of 1 with the
concentration of 0.2 M (HOAc/Ac2O = 1:1), Pd(OAc)2 (5 mol %),
b
PhI(OAc)2(1.1 equiv) at 100 °C for 6 h. Hydrazine monohydrate,
c
d
e
THF, 25 °C. The reaction time is 4 h. NMR yield. 0.12 mmol of 1
was used.
yields. The reaction exhibited very good regio-selectivity so
that only less crowded product 2c (68% yield) was furnished
for m-toluidine. Various halogen substituted anilines also
successfully delivered acceptable to good yield (2e−2k, 60%−
73% yields). Because of the difficulty in separation, compound
2h was directly mixed with hydrazine monohydrate to give 2h′
in a overall yield of 55%. Substrates with an electron-
withdrawing group, such as MeCOO-, CF3-, -OCF3 groups,
afforded the desired products (2l, 58%; 2m, 56%, 2n 31%
yield) in low yield with than the tested amines with an
electron-donating group or without substitutions. It is
worthwhile to mention that extending the reaction time will
lead to lower yields for electron deficient substrates, indicating
thermal decomposition of the corresponding products under
acidic condition at high temperature. Ts-protected amine
group can be tolerated to give product 2o in 26% NMR yield.
Isolation of the product was met with limited success due to its
high polarity and contamination with unknown byproducts.
Compounds with protected secondary amines smoothly
underwent Pd-catalyzed C−H acetoxylation, providing the
desired product in good yields (2p, 69%; 2q, 73% yield). It was
encouraging to observe that the reaction was applicable to
heterocyclic substrates as well. Indeed, the transformation was
effective on indole, benzothiophene, and quinoline derivatives,
CONCLUSIONS
■
In summary, we have developed a convenient and efficient
synthetic methodology for the synthesis of 2-amino phenol
derivatives, which are key structural motifs of numerous
bioactive compounds and blockbuster drugs. The nitro-
pyrimidine directing group can be introduced and removed
easily, facilitating a wide range of function group tolerance.
Moreover, introduction/removal of the directing group and
the C−H functionalization sequence can be integrated in one
pot. More applications of the directing group for step-efficient
synthesis of biologically interesting molecules are under way.
EXPERIMENTAL SECTION
■
Attempt To Use Pyridine Unit as a DG. Under N2 atmosphere,
an oven-dried 25 mL flask was charged with N-phenylpyridin-2-amine
(0.170 g, 1.00 mmol, 1.00 equiv), AcOH (6.0 mL) and Ac2O (2.0
mL), followed by the addition of Pd(OAc)2 (5.60 mg, 0.05 mmol,
0.05 equiv) and PhI(OAc)2 (0.365 g, 1.10 mmol, 1.10 equiv). After it
was stirred for 20 h at 100 °C, the reaction mixture was concentrated
under vacuo. The residue was purified by column chromatography on
silica gel (PE/EtOAc = 5/1 to 2/1 as the eluent) to give compound
S1 (yellow solid, 0.08 3 g, 0.39 mmol, 39% yield) and S3 (white solid,
0.050 g, 0.30 m10 mol, 30% yield). Compound S1, Rf = 0.25 (PE/
EtOAc = 2/1(v/v)). NMR spectroscopy: 1H NMR (300 MHz,
C
DOI: 10.1021/acs.organomet.9b00113
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CDCl3, 25 °C, δ): 8.43 (dd, J = 3.0 Hz, J = 6.0 Hz, 1 H), 7.71 (t, J =
3.0 Hz, J = 6.0 Hz, 1 H), 7.46 (d, J = 8.7 Hz, 1 H), 7.41 (d, J = 8.7 Hz,
1 H), 7.36−7.28 (m, 3 H), 7.13 (dd, J = 3.0 Hz, J = 6.0 Hz, 1 H), 2.11
(s, 3 H). Compound S3, Rf = 0.15 (PE/EtOAc = 1/1(v/v)). NMR
spectroscopy: 1H NMR (300 MHz, CDCl3, 25 °C, δ): 8.46 (d, J = 6.0
Hz, 1 H), 7.93 (dd, J = 9.0 Hz, J = 12.0 Hz, 2 H), 7.71 (d, J = 8.7 Hz,
1 H), 7.54 (t, J = 6 Hz, J = 15 Hz, 1 H), 7.46−7.35 (m, 2 H), 6.86 (t,
J = 6.0 Hz, J = 15.0 Hz, 1 H). Compounds S1 and S3 are known.68
Attempt To Use Pyrimidine Unit as a DG. Under N2
atmosphere, an oven-dried 25 mL flask was charged with N-
phenylpyrimidin-2-amine (0.136 g, 0.80 mmol, 0.80 equiv), AcOH
(6.0 mL), and Ac2O (2.0 mL), followed by addition of Pd-
(OAc)2(4.48 mg, 0.04 mmol, 0.05 equiv) and PhI(OAc)2(0.320 g,
0.88 mmol, 1.10 equiv). After it was stirred for 20 h at 100 °C, the
reaction mixture was concentrated under vacuo. The residue was
purified by column chromatography on silica gel (PE/EtOAc = 2/1 to
PE/EtOAc = 1/1 as the eluent) to give the title compound S2 (dark
brown solid, 0.094 g, 55 mmol, 55% yield) and S4 (dark brown solid,
0.062 g, 37 mmol, 37% yield). S2: Rf = 0.32 (PE/EtOAc = 2/1(v/v)).
3-Methoxy-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2d). According to the representative reaction procedure (I): Brown
solid (0.191 g, 0.63 mmol, 63% yield); Rf = 0.47 (PE/EtOAc = 5/
1(v/v)). NMR spectroscopy: 1H NMR (300 MHz, CDCl3, 25 °C, δ):
9.20 (s, 2 H), 8.46 (d, J = 8.7 Hz, 1 H), 8.27 (s, 1 H), 6.77 (dd, J =
2.4 Hz, 8.7 Hz, 1 H), 6.73 (d, J = 2.4 Hz, 1 H), 3.92 (s, 3 H), 2.32 (s,
3 H). 13C NMR (75 MHz, CDCl3, 25 °C,δ): 169.7, 160.9, 155.0,
149.3, 133.3, 126.7, 124.8, 120.4, 113.6, 104.9, 56.2, 21.2. Mass
spectrometry: HRMS (ESI-TOF) (m/z): calcd for C13H13N4O5+ ([M
+ H]+), 305.0880; found, 305.0883.
5-Fluoro-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2e). According to the representative reaction procedure (I): Light
yellow solid (0.213 g, 0.73 mmol, 73% yield); Rf = 0.59 (PE/EtOAc =
1
5/1(v/v)). NMR spectroscopy: H NMR (300 MHz, CDCl3,25 °C,
δ): 9.17 (s, 2 H), 8.11- 8.05 (m, 1 H), 7.54 (s, 1 H), 7.08−6.99 (m, 2
H), 2.35 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25 °C,δ): 168.3,
161.6, 158.2, 155.2, 143.1 (t, J = 11.3 Hz), 136.3, 125.7 (t, J = 3.8
Hz), 125.2 (t, J = 9.0 Hz), 113.5 (t, J = 21.6 Hz), 110.7 (t, J = 25.5
Hz), 21.1. Mass spectrometry: HRMS (ESI-TOF) (m/z): calcd for
+
C12H10FN4O4 ([M + H]+), 293.0681; found, 293.0677. 19F NMR
1
NMR spectroscopy: H NMR (300 MHz, CDCl3, 25 °C, δ): 8.68
(75 MHz, CDCl3, 25 °C,δ): −114.1.
(dd, J = 3.0 Hz, J = 6.0 Hz, 1 H), 7.47−7.42 (m, 2 H), 7.37 (d, J = 6.0
Hz, 2 H), 7.30−7.26 (m, 2 H), 7.11 (t, J = 3.0 Hz, J = 9.0 Hz, 1 H),
2.32 (s, 3 H). S4: Rf= 0.12 (PE/EtOAc = 1/1(v/v)). NMR
5-Chloro-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2f). According to the representative reaction procedure (I): Light
yellow solid (0.204 g, 0.66 mmol, 66% yield). Rf= 0.56 (PE/EtOAc =
1
spectroscopy: H NMR (300 MHz, CDCl3, 25 °C, δ): 9.53 (dd, J =
1
5/1(v/v)). NMR spectroscopy: H NMR (300 MHz, CDCl3,25 °C,
3.0 Hz, J = 6.0 Hz, 1 H), 8.84 (dd, J = 3.0 Hz, J = 6.0 Hz, 1 H), 8.42
(d, J = 8.7 Hz, 1 H), 7.87 (d, J = 8.7 Hz, 1 H), 7.57 (t, J = 6 Hz, J = 15
Hz, 1 H), 7.44 (t, J = 6.0 Hz, J = 15.0 Hz, 1 H), 7.16 (dd, J = 6.0 Hz, J
= 9.0 Hz, 1 H). Compounds S2 and S4 are known.69
δ): 9.20 (s, 2 H), 8.21 (d, J = 8.7 Hz, 1 H), 7.64 (s, 1 H), 7.31−7.26
(m, 1 H), 2.38 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25 °C,δ): 168.3,
161.2, 155.2, 141.9, 130.4, 128.2, 126.8, 123.9, 123.1, 21.1. Mass
+
spectrometry: HRMS (ESI-TOF) (m/z): calcd for C12H10ClN4O4
Representative Reaction Procedure (I): Synthesis of 2-((5-
Nitropyrimidin-2-yl)amino) Phenylacetate (2a). Under N2
atmosphere, an oven-dried 50 mL flask was charged with the aniline
(0.0931 g, 1.00 mmol, 1.00 equiv) and 2-chloro-5-nitropyrimidine
(0.1593 g, 1.00 mmol, 1.00 equiv) in CH3CN (2.0 mL, 0.50 M). The
reaction mixture was stirred for 4 h at rt, and the reaction was
monitored via TLC until the disappearance of 2-chloro-5-nitro-
pyrimidine (Rf = 0.79 (PE/EtOAc = 5/1 (v/v)). AcOH (4.0 mL) and
Ac2O (4.0 mL) (AcOH/Ac2O = 1/1) were directly added to the
reaction mixture, followed by Pd(OAc)2 (11.2 mg, 0.05 mmol, 0.05
equiv) and PhI(OAc)2 (0.3482 g, 0.21 mmol, 1.10 equiv). The
reaction was cooled to rt after stirring at 100 °C for 6 h, which was
concentrated by reduced pressure. The residue was purified by
column chromatography (PE/EtOAc = 25/1 to 5/1(v/v)) to afford
2a as a brown solid (0.204 g, 0.75 mmol, 75% yield). Rf = 0.54 (PE/
([M + H]+), 309.0385; found, 309.0385.
5-Bromo-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2g). According to the representative reaction procedure (I): Light
yellow solid (0.250 g, 0.71 mmol, 71% yield). Rf= 0.53 (PE/EtOAc =
1
5/1(v/v)). NMR spectroscopy: H NMR (300 MHz, CDCl3,25 °C,
δ): 9.20 (s, 2 H), 8.18 (d, J = 8.7 Hz, 1 H), 7.64 (s, 1 H), 7.46−7.38
(m, 2 H), 2.38 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25 °C,δ): 168.3,
161.1, 155.2, 141.9, 136.4, 129.7, 128.8, 125.9, 124.1, 117.6, 21.1.
Mass spectrometry: HRMS (ESI-TOF) (m/z): calcd for
+
C12H10BrN4O4 ([M + H]+), 352.9880; found, 352.9875.
2-Amino-5-iodophenol (2h′). According to the representative
reaction procedure (I), crude compound 2h was obtained as a brown
solid (0.240 g) which was dissolved in THF (2.50 mL, 0.20 M).
Hydrazine monohydrate (0.05 g, 1.0 mmol, 2.0 equiv) was added
dropwise, and the reaction was stirred for 30 min at 25 °C. The
reaction mixture was monitored via TLC until the disappearance of
starting material (Rf = 0.55 (PE/EtOAc = 5/1 (v/v)). The reaction
was quenched by water and extracted with ethyl acetate (10 mL δ 3).
The combined organic layer was washed with brine, dried over
anhydrous MgSO4, and concentrated under reduced pressure. The
residue was purified by column chromatography on silica gel (PE/
EtOAc = 2:1 as an eluent) to give 2h′ as light yellow solid (0.129 g,
0.55 mmol, 55% yield); Rf = 0.25 (PE/EtOAc = 2/1(v/v)). NMR
spectroscopy: 1H NMR (300 MHz, DMSO-d6, 25 °C, δ): 9.40 (brs, 1
H), 6.89 (d, J = 1.7 Hz, 1H). 6.82 (dd, J = 8.1, 1.7 Hz, 1H), 6.40 (d, J
= 8.1 Hz, 1H), 4.69 (brs, 2H). 13C NMR (101 MHz, CDCl3, 25 °C,
δ): 145.4, 136.9, 127.9, 122.1, 116.2, 75.8. Mass spectrometry: HRMS
(ESI-TOF) (m/z): calcd for C6H7INO+ ([M + H]+), 235.9567;
found, 235.9561.
1
EtOAc = 5/1). NMR spectroscopy: H NMR (300 MHz, CDCl3, 25
°C,δ): (ppm) 9.19 (s, 2 H), 8.19 (d, J = 7.7 Hz, 1 H), 7.71 (s, 1 H),
7.35−7.29 (m, 1 H), 7.25−7.21 (m, 2 H), 2.37 (s, 3 H). 13C NMR
(75 MHz, CDCl3, 25 °C,δ): 168.8, 161.4, 155.1, 141.9, 136.1, 129.4,
126.6, 126.0, 123.5, 122.7, 21.2. Mass spectrometry: HRMS (ESI-
TOF) (m/z): calcd for C12H11N4O4+ ([M + H] +), 275.0775; found,
275.0771.
3-Methyl-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2b). According to the representative reaction procedure (I): Light
brown solid (0.207 g, 0.72 mmol, 72% yield); Rf = 0.52 (PE/EtOAc =
5/1(v/v)). NMR spectroscopy: 1H NMR (300 MHz, CDCl3, 25
°C,δ): 9.16 (s, 2 H), 7.76 (d, J = 8.7 Hz, 1 H), 7.41 (s, 1 H), 7.05−
6.98 (m, 2 H), 2.32 (s, 3 H), 2.31 (s, 3 H). 13C NMR (75 MHz,
CDCl3, 25 °C,δ): 169.8, 162.2, 155.4, 148.7, 135.9, 133.2, 132.9,
131.1, 125.4, 123.9, 120.0, 21.3, 18.3. Mass spectrometry: HRMS
+
+
3-Fluoro-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2i). According to the representative reaction procedure (I): Brown
solid (0.198 g, 0.68 mmol, 68% yield); Rf = 0.42 (PE/EtOAc = 3/
1(v/v)). NMR spectroscopy: 1H NMR (300 MHz, CDCl3, 25 °C, δ):
9.31 (s, 2 H), 7.48−7.39(m,1H), 7.32−7.26 (m, 1 H), 7.25−7.18 (m,
2 H), 2.63 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25 °C,δ): 172.0,
162.7, 159.9, 156.5, 154.3, 138.3, 130.6 (t, J = 8.3 Hz), 130.3, 125.1
(t, J = 3.8 Hz), 116.9 (t, J = 19.5 Hz), 26.6. Mass spectrometry:
(ESI-TOF) (m/z): calcd for C13H13N4O4 ([M + H] ), 289.0931;
found, 289.0930.
2-Methyl-6-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2c). According to the representative reaction procedure (I): Light
yellow solid (0.195 g, 0.68 mmol, 68% yield); Rf = 0.53 (PE/EtOAc =
5/1(v/v)). NMR spectroscopy: 1H NMR (300 MHz, CDCl3, 25
°C,δ): 9.19 (s, 1H), 7.95 (s, 1H), 7.63 (s, 1H), 7.11−7.04 (m, 2H),
2.40 (s, 3H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3, 25 °C,δ):
169.1, 161.5, 155.2, 140.0, 136.7, 136.1, 129.0, 126.8, 124.2, 122.3,
21.4, 21.1. Mass spectrometry: HRMS (ESI-TOF) (m/z): calcd for
+
HRMS (ESI-TOF) (m/z): calcd for C12H10FN4O4 ([M + H] +),
293.0681; found, 293.0680. 19F NMR (75 MHz, CDCl3, 25 °C,δ):
−121.88.
+
+
C13H13N4O4 ([M + H] ), 289.0931; found, 289.0927.
D
DOI: 10.1021/acs.organomet.9b00113
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3-Bromo-2-((5-nitropyrimidin-2-yl)amino) Phenylacetate
(2j). According to the representative reaction procedure (I): Light
yellow solid (0.229 g, 0.65 mmol, 65% yield); Rf = 0.51, (PE/EtOAc
= 5/1(v/v)). NMR spectroscopy: 1H NMR (300 MHz, CDCl3,25 °C,
δ): 9.31 (s, 2 H), 7.73 (d, J = 7.8 Hz, 1 H), 7.46 (t, J = 7.5 Hz, 1 H),
7.38−7.26 (m, 2 H), 2.62 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25
°C, δ): 171.9, 162.3, 154.2, 139.5, 138.1, 133.8, 130.6, 130.3, 128.9,
123.7, 26.9. Mass spectrometry: HRMS (ESI-TOF) (m/z): calcd for
Reddish brown solid (0.205 g, 0.51 mmol, 51% yield); Rf = 0.24 (PE/
EtOAc = 2/1(v/v)). 1H NMR (300 MHz, CDCl3, 25 °C, δ): 9.15 (s,
2 H), 7.90 (s, 1H), 7.83 (s, 1 H), 7.55 (d, J = 8.4 Hz, 1H), 7.36 (s, 1
H), 7.32−7.30 (m, 3 H), 7.17 (d, J = 7.1 Hz, 1H), 7.12 (d, J = 8.6 Hz,
1 H), 5.28 (s, 2 H), 2.36 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25 °C,
δ): 168.6, 161.3, 155.2, 137.0, 135.4, 133.4, 132.5, 130.0, 129.0, 128.0,
127.1, 118.5, 118.2, 114.6, 102.8, 50.5, 21.1. HRMS (ESI-TOF) (m/
+
z): calcd for C21H18N5O4 ([M + H]+), 404.1353, found, 404.1358.
+
C12H10BrN4O4 ([M + H]+), 352.9880; found, 352.9876.
5-((5-Nitropyrimidin-2-yl)amino) Benzo [b] thiophen-4-yl
Acetate (2t). According to the representative reaction procedure (I):
Light yellow solid (0.204 g, 0.62 mmol, 62% yield); Rf = 0.47 (PE/
EtOAc = 2/1(v/v)). 1H NMR (300 MHz, CDCl3, 25 °C,δ): 9.18 (s, 2
H), 7.93 (d, J = 8.7 Hz, 1 H), 7.82 (d, J = 8.6 Hz, 1 H), 7.80 (s, 1 H),
7.52 (d, J = 5.5 Hz, 1 H), 7.23 (d, J = 5.5 Hz, 1 H), 2.45 (s, 3 H). 13C
NMR (101 MHz, CDCl3, 25 °C,δ): 168.6, 162.0, 155.4, 139.1, 138.0,
133.8, 128.8, 125.6, 121.9, 120.8, 120.0, 21.0. HRMS (ESI-TOF) (m/
z): calcd for C14H11N4O4S+ ([M + H]+), 331.0496, found, 331.0494.
Procedure for Synthesis of 2-Amino-5-chlorophenol (2f′).
Under N2 atmosphere, an oven-dried 25 mL flask was charged with
the 5-chloro-2-((5-nitropyrimidin-2-yl)amino) phenylacetate (0.154
g, 0.5 mmol, 1.0 equiv) in THF (2.50 mL, 0.20 M). Hydrazine
monohydrate (0.05 g, 1.0 mmol, 2.0 equiv) was added dropwise, and
the reaction was stirred for 30 min at 25 °C. The reaction mixture was
monitored via TLC until the disappearance of starting material (Rf =
0.20 (PE/EtOAc = 5/1 (v/v)). The reaction was quenched by water
and extracted with ethyl acetate (10 mL ⊆ 3). The combined organic
layer was washed with brine, dried over anhydrous MgSO4, and
concentrated under reduced pressure. The residue was purified by
column chromatography on silica gel (PE/EtOAc = 5:1 to 2:1 as an
eluent) to give 2f′ as dark brown solid (0.082 g, 0.44 mmol, 88%
2,4-difluoro-6-((5-nitropyrimidin-2-yl)amino) Phenylace-
tate (2k). According to the representative reaction procedure (I):
Light yellow solid (0.189 g, 0.61 mmol, 61% yield); Rf = 0.54 (PE/
EtOAc = 5/1(v/v)). NMR spectroscopy: 1H NMR (300 MHz,
CDCl3,25 °C, δ): 9.25 (s, 2 H), 8.16 (dt, J = 2.4 Hz, 10.7 Hz, 1 H),
7.82 (s, 1 H), 6.77−6.69 (m, 1 H), 2.44 (s, 3 H). 13C NMR (75 MHz,
CDCl3, 25 °C, δ): 167.5, 160.7, 158.4 (t, J = 6.0 Hz), 156.0 (t, J =
15.0 Hz), 155.0, 136.8, 132.3 (tt, J = 4.5 Hz, 14.3 Hz), 125.1 (t, J = 21
Hz), 104.1 (tt, J = 3.8 Hz, 29.3 Hz), 100.3 (tt, J = 2.3 Hz, 27.8 Hz),
20.4. Mass spectrometry: HRMS (ESI-TOF) (m/z): calcd for
+
C12H9F2N4O4 ([M + H]+), 311.0586; found, 311.0574. 19F NMR
(75 MHz, CDCl3, 25 °C,δ): −110.9, −122.8.
Methyl 3-acetoxy-4-((5-nitropyrimidin-2-yl)amino)-
benzoate (2l). According to the representative reaction procedure
(I): Light yellow solid (0.193 g, 0.58 mmol, 58% yield); Rf = 0.53
1
(PE/EtOAc = 2/1(v/v)). NMR spectroscopy: H NMR (300 MHz,
CDCl3,25 °C, δ): 9.19 (s, 1H), 7.95 (s, 1H), 7.63 (s, 1H), 7.11−7.04
(m, 2H), 2.40 (s, 3H) 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3, 25
°C, δ): 168.8, 165.2, 161.2, 155.1, 142.2, 136.1, 134.8, 126.6, 126.0,
124.4, 124.3, 52.3, 21.2. Mass spectrometry: HRMS (ESI-TOF) (m/
+
z): calcd for C14H13N4O6 ([M + H]+), 333.0830; found, 333.0836.
1
2-((5-Nitropyrimidin-2-yl) amino)-5-(trifluoromethoxy) Phe-
nylacetate (2m). According to the representative reaction procedure
(I): Light yellow solid (0.191 g, 0.56 mmol, 56% yield); Rf = 0.35
yield); Rf = 0.28 (PE/EtOAc = 5/1(v/v)). NMR spectroscopy: H
NMR (300 MHz, CDCl3, 25 °C, δ): 6.78−6.72 (m, 2 H), 6.70−6.63
(m, 1 H). 13C NMR (75 MHz, CDCl3, 25 °C, δ): 145.3, 134.0, 122.1,
119.4, 115.7, 115.0. Compound 2f′ is known.76
1
(PE/EtOAc = 5/1(v/v)). H NMR (300 MHz, CDCl3, 25 °C, δ):
9.25 (s, 2 H), 8.57 (d, J = 8.6 Hz, 1 H), 7.85 (s, 1 H), 7.56 (d, J = 8.7
Hz, 1 H), 7.52 (s, 1 H), 2.43 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25
°C,δ): 168.3, 160.9, 155.1, 140.3, 136.7, 132.8, 127.0, 126.5, 123.6 (J
= 15.1 Hz), 122.0, 120.0 (J = 15.6 Hz), 21.2. 19F NMR (75 MHz,
CDCl3, 25 °C,δ): −62.2. HRMS (ESI-TOF) (m/z): calcd for
2-Amino-5-bromophenol (2g′). The same procedure as
obtaining 2f′: Dark brown solid (0.0855 g, 0.45 mmol, 91% yield);
Rf= 0.31 (PE/EtOAc = 5/1(v/v)). NMR spectroscopy: 1H NMR
(300 MHz, (CD3)2SO, 25 °C, δ): 9.49 (brs, 1H), 6.77 (d, J = 2.2 Hz,
1H), 6.68 (dd, J = 8.3, 2.2 Hz, 1H), 6.53 (d, J = 8.3 Hz, 1H), 4.7 (brs,
2H). 13C NMR (75 MHz, (CD3)2SO, 25 °C,δ): 145.2, 136.4 121.9,
116.7, 115.4, 106.2. Compound 2g′ is known.77
+
C13H10F3N4O4 ([M + H]+), 343.0649, found, 343.0643.
1-(5-Nitropyrimidin-2-yl)-1, 2, 3, 4-tetrahydroquinolin-8-yl
Acetate (2p). According to the representative reaction procedure
(I): Reddish brown solid (0.216 g, 0.69 mmol, 69% yield); Rf = 0.52
(PE/EtOAc = 5/1(v/v)). 1H NMR (300 MHz, (CD3)2SO, 25 °C, δ):
9.15 (s, 2 H), 7.29−7.23 (t, J = 15.4 Hz, 1 H), 7.17 (d, J = 6.0 Hz,
1H), 7.09 (dd, J = 1.4 Hz, J = 7.9 Hz, 1 H), 2.75 (s, 2 H), 1.99 (s, 2
H), 1.86 (s, 3 H), 1.24 (m, 2 H) 13C NMR (75 MHz, CDCl3, 25 °C,
δ): 168.3, 161.3, 154.6, 144.8, 136.3, 135.2, 131.1, 126.9, 125.8, 121.0,
45.6, 26.3, 24.1, 21.1. HRMS (ESI-TOF) (m/z): calcd for
Gram-Scale Synthesis of Compound 2g. Under N2 atmos-
phere, an oven-dried 250 mL flask was charged with 4-bromoaniline
(1.03 g, 6.0 mmol, 1.0 equiv) and 2-chloro-5-nitropyrimidine (0.96 g,
6.0 mmol, 1.0 equiv) in CH3CN (9.0 mL, 1.50 M). The reaction
mixture was stirred for 4 h at room temperature, which was monitored
via TLC until the disappearance of 2-chloro-5-nitropyrimidine (Rf =
0.79, (PE/EtOAc = 5/1 (v/v)). AcOH (12.0 mL) and Ac2O (12.0
mL) were directly added to the reaction mixture, followed by
Pd(OAc)2 (67.2 mg, 0.3 mmol, 0.05 equiv) and PhI(OAc)2 (2.19 g,
6.6 mmol, 1.10 equiv). After stirring for 10 h at 100 °C, the reaction
mixture was concentrated under vacuo, purified by column
chromatography (eluent, PE/EtOAc = 25/1 to 5/1(v/v)) to give
the desired product as light yellow solid (1.12 g, 3.66 mmol, 61%
yield). Rf = 0.52 (PE/EtOAc = 5/1(v/v)).
One-Pot Procedure for Synthesis of Compound 2g′. Under
N2 atmosphere, an oven-dried 25 mL flask was charged with 4-
bromoaniline (0.172 g, 1.00 mmol, 1.00 equiv) and 2-chloro-5-
nitropyrimidine (0.159 g, 1.0 mmol, 1.00 equiv) in CH3CN (1.50 mL,
1.50 M). The reaction mixture was stirred for 4 h at room
temperature, which was monitored via TLC until the disappearance
of 2-chloro-5-nitropyrimidine (Rf = 0.79, (PE/EtOAc = 5/1 (v/v)).
AcOH (2.0 mL) and Ac2O (2.0 mL) were directly added to the
reaction mixture, followed by Pd(OAc)2 (5.60 mg, 0.05 mmol, 0.05
equiv) and PhI(OAc)2 (0.365 g, 1.10 mmol, 1.10 equiv). After it was
stirred for 6 h at 100 °C, the reaction mixture was concentrated under
vacuo, which was redissolved in THF (2.50 mL, 0.20 M). Hydrazine
monohydrate (101 mg, 2 mmol) was added dropwise. After stirring at
25 °C for 30 min. The reaction was concentrated under vacuo, diluted
with water (10 mL), extracted with ethyl acetate (10 mL ⊆ 3). The
+
C15H15N4O4 ([M + H]+), 315.1088, found, 315.1080.
2-(Methyl (5-nitropyrimidin-2-yl)amino) Phenylacetate
(2q). According to the representative reaction procedure (I): Yellow
brown solid (0.210 g, 0.73 mmol, 73% yield); Rf = 0.47 (PE/EtOAc =
1
5/1(v/v)). H NMR (300 MHz, CDCl3, 25 °C, δ): 9.19 (d, J = 3.1
Hz, 1 H), 9.00 (d, J = 3.18 Hz, 1 H), 7.45−7.34 (m, 3 H), 7.26−7.23
(m, 1 H), 3.53 (s, 3 H), 2.09 (s, 3 H). 13C NMR (75 MHz, CDCl3, 25
°C,δ): 168.7, 162.4, 154.9, 146.5, 136.0, 134.9, 129.2, 128.3, 127.3,
123.9, 39.0, 20.8. HRMS (ESI-TOF) (m/z): calcd for
+
C13H13N4O4 ([M + H]+), 289.0931, found, 289.0933
1-Benzyl-6-((5-nitropyrimidin-2-yl)amino)-1H-indol-5-yl Ac-
etate (2r). According to the representative reaction procedure (I):
Reddish brown solid (0.233 g, 0.58 mmol, 58% yield); Rf = 0.24 (PE/
EtOAc = 2/1(v/v)). 1H NMR (400 MHz, DMSO, 25 °C,δ): 10.84 (s,
1 H), 9.18 (s, 2 H), 8.01 (s, 1 H), 7.57 (s, 1 H), 7.41 (d, J = 8.5 Hz, 1
H), 7.35−7.31 (m, 3 H), 7.28−7.26 (m, 3 H), 5.34 (s, 2 H), 2.33 (s, 3
H). 13C NMR (101 MHz, DMSO, 25 °C,δ): 168.5, 161.0, 155.1,
137.8, 134.7, 133.3, 132.9, 128.8, 128.6, 127.5, 120.3, 118.4, 117.5,
117.2, 114.5, 102.8, 49.2, 20.7. HRMS (ESI-TOF) (m/z): calcd for
+
C21H18N5O4 ([M + H]+), 404.1353, found, 404.1363.
1-Benzyl-5-((5-nitropyrimidin-2-yl)amino)-1H-indol-6-yl Ac-
etate (2s). According to the representative reaction procedure (I):
E
DOI: 10.1021/acs.organomet.9b00113
Organometallics XXXX, XXX, XXX−XXX

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Article
combined organic layer was washed with brine, dried over anhydrous
MgSO4, and concentrated. The residue was purified by column
chromatography on silica gel (PE/EtOAc = 5/1 to 2/1 as an eluent)
to give 2g′ as a dark brown solid (0.097 g, 52 mmol, 52% yield).
Phenethylamines, Benzylamines, and 2-Aryl Anilines. J. Am. Chem.
Soc. 2017, 139, 417−425.
(12) Li, G.-C.; Wang, P.; Farmer, M. E.; Yu, J.-Q. Ligand-Enable
Auxiliary-Free meta-C-H Arylation of Phenylacetic Acids. Angew.
Chem. 2017, 129, 6978−6981.
ASSOCIATED CONTENT
* Supporting Information
(13) Cheng, G.; Wang, P.; Yu, J.-Q. meta-C-H Arylation and
Alkylation of Benzylsulfonamide Enable by a Palladium(II)/Isoquino-
line Catalyst. Angew. Chem., Int. Ed. 2017, 56, 8183−8186.
(14) Park, Y.; Niemeyer, Z. L.; Yu, J.-Q.; Sigman, M. S. Quantifying
Structural Effects of Amino Acid Ligands in Pd(II)-Catalyzed
Enantioselective C-H Functionalization Reactions. Organometallics
2018, 37, 203−210.
(15) Hale, L. V. A.; Emmerson, D. G.; Ling, E. F.; Roering, A. J.;
Ringgold, M. A.; Clark, T. B. An ortho-directed C-H Borylation/
Suzuki Coupling Sequence in the Formation of Biphenylbenzylic
Amines. Org. Chem. Front. 2015, 2, 661−664.
(16) Xu, W.; Pek, J. H.; Yoshikai, N. Cobalt-Catalyzed, Imine-
Directed Olefin Hydroarylation under Grignard-free Conditions. Adv.
Synth. Catal. 2016, 358, 2564−2568.
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.organo-
met.9b00113.
NMR spectra and chemical structures of new com-
pounds (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: pfeng@jnu.edu.cn.
■
ORCID
(17) Li, Z.-Y.; Wang, G.-W. Palladium-Catalyzed Decarboxylative
Ortho-Ethoxycarbonylation of O-Methyl Ketoximes and 2-Arypyr-
idines with Potassium Oxalate Monoester. Org. Lett. 2015, 17, 4866−
4869.
(18) Muniraj, N.; Prabhu, K. R. Cobalt(III)-Catalyzed C-H
Activation: Azo Directed Selective 1,4-Addition of Ortho C-H Bond
to Maleimides. J. Org. Chem. 2017, 82, 6913−6921.
(19) Neufeldt, S. R.; Sanford, M. S. Controlling Site Selectivity in
Palladium-Catalyzed C-H Bond Functionalization. Acc. Chem. Res.
2012, 45, 936−946.
(20) Wang, G.-W.; Yuan, T.-T.; Li, D.-D. One-pot Formation of C-C
and C-N bonds through Palladium-Catalyzed Dual C-H Activation:
Synthesis of Phenanthridinones. Angew. Chem., Int. Ed. 2011, 50,
1380−1383.
Pengju Feng: 0000-0002-5470-0403
Author Contributions
#J.Z. and Y.H. contributed equally.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank Dr. Yang Zhao of Francool® Technologies for useful
discussions and advice. This work was supported by the
National Natural Science Foundation of China (No.
21602078), “the Fundamental Research Funds for the Central
Universities” (11617432), Innovation Projects of Universities
in Guangdong Province (217 KTSCX011) and Jinan
University.
(21) Jing, K.; Yao, J.-P.; Li, Z.-Y.; Li, Q.-L.; Lin, H.-S.; Wang, G.-W.
Palladium-Catalyzed Decarboxylative ortho-Acylation of Benzamides
with Oxocarboxylic acid. J. Org. Chem. 2017, 82, 12715−12725.
(22) Jing, K.; Wang, X.-N.; Wang, G.-W. Diastereoselective
Synthesis of Oxazoloisoindolinones via Cascade Pd-catalyzed ortho-
Acylation of N-Benzoyl Amino Acid Derivatives and Subsequent
Double Intramolecular Cyclizations. J. Org. Chem. 2019, 84, 161−172.
(23) Liu, G.; Shen, Y.; Zhou, Z.; Lu, X. Rhodium(III)-Catalyzed
Redox-Neutral Coupling of N-Phenoxyacetamides and Alkynes with
Tunable Selectivity. Angew. Chem., Int. Ed. 2013, 52, 6033−6037.
(24) Kianmehr, E.; Fardpour, M.; Kharat, N. Palladium-Catalyzed
Chemo- and Regioselective Oxidative Cross-Dehydrogenative Cou-
pling of Acetanilides with Benzothiazole. Eur, J. Org, Chem. 2017,
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