Palladium-catalyzed ortho-selective C-H bond chlorination of aromatic ketones

Article abstract of DOI:10.1016/j.cclet.2015.07.011

A palladium-catalyzed ortho-selective C-H bond chlorination reaction for the preparation of 2-chloro aromatic ketones was described. Both electron-withdrawing and electron-donating groups on the aromatic rings are well tolerated under the optimized conditions. The 2-chloro aromatic ketones obtained by our method could be applied to synthesize the derivatives of 1H-indazole or benzo[d]isoxazole.

Full text of DOI:10.1016/j.cclet.2015.07.011

G Model
CCLET 3388 1–5
Chinese Chemical Letters xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
1
2
Original article
3
4
Palladium-catalyzed ortho-selective C–H bond chlorination of
aromatic ketones
a,
Q1 Gang Shan b,1, Gui-Yi Huang a,b,1, Yu Rao b, , Hui Zhang
*
*
5
6
7
8
a School of Pharmaceutical Engineering, Shenyang Pharmaceutical University, Shenyang 110016, China
b MOE Key Laboratory of Protein Sciences, Department of Pharmacology and Pharmaceutical Sciences, School of Medicine and School of Life Sciences,
Tsinghua University, Beijing 100084, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A palladium-catalyzed ortho-selective C–H bond chlorination reaction for the preparation of 2-chloro
aromatic ketones was described. Both electron-withdrawing and electron-donating groups on the
aromatic rings are well tolerated under the optimized conditions. The 2-chloro aromatic ketones
obtained by our method could be applied to synthesize the derivatives of 1H-indazole or
benzo[d]isoxazole.
Received 25 April 2015
Received in revised form 17 June 2015
Accepted 24 June 2015
Available online xxx
ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
Palladium catalysis
C–H chlorination
Aromatic ketones
9
10
1. Introduction
our continuous studies toward transition-metal-catalyzed C(sp2)– 30
H halogenation reactions [6], we envisioned that 2-chloro aromatic 31
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
2-Chloro aromatic ketones serve as versatile building blocks
for the synthesis of various heterocycles, such as derivatives of
indazoles, derivatives of benzo[d]isoxazoles, derivatives of indoles,
derivatives of quinolinone, derivatives of benzo[b]thiophenes and
derivatives of benzo[d]isothiazoles, etc. [1]. Moreover, introducing
chlorine atom on drug candidates is a commonly used strategy to
modulate the bioactivities of these molecules [2].
Traditionally, there are mainly two approaches (Scheme 1) for
the synthesis of 2-chloro aromatic ketones: (1) early-stage
introducing chlorine atom on the starting material for aromatic
ketone synthesis [3], such as Friedel–Crafts acylation; (2) late-
stage introducing chlorine atom on the ketone molecules through
functional group transformations, such as the widely used
Sandmeyer reaction [4]. Both strategies rely on pre-functionaliza-
tion of the starting material for aromatic ketone synthesis, which
usually involve a multi-step process to assemble the targeted
ketone molecules. In recent years, transition-metal-catalyzed
C(sp2)–H activation reactions have received more and more
attention, which are atom economic and step economic [5]. In
ketones could be accessed through palladium-catalyzed ortho- 32
selective C(sp2)–H chlorination of aromatic ketones under proper 33
conditions (Scheme 1).
34
2. Experimental
35
36
2.1. Optimization of reaction conditions
We chose benzophenone (1a) as the substrate to explore the 37
reaction conditions (Table 1). The reaction was initiated with 38
Pd(OAc)2 as catalyst, NCS as chlorination reagent, and DCE as 39
solvent. After being stirred at 80 8C for 10 h, no desired chlorination 40
product (1b) was observed and all of the starting material 41
remained (entry 1). Based on our experience and understanding 42
of weak coordination [7], we believed that suitable acid could 43
possibly promote this reaction. Then we began to screen weak and 44
strong acids. Delightfully, when 1.0 equiv. of TfOH was added, the 45
desired chlorination product (1b) was obtained in 85% 1H NMR 46
yield (entry 4), with minor amount of unknown side products. In 47
contrast, AcOH and TFA were ineffective. Subsequential co- 48
oxidants screening found that the 1H NMR yield of (1b) could 49
be further improved to 95% in the presence of K2S2O8 (entry 6). 50
Na2S2O8 and (NH4)2S2O8 gave similar results (entry 5 and 7). 51
Without palladium catalyst, there was no reaction (entry 8). Other 52
palladium catalysts, such as Pd(MeCN)Cl2, gave relatively low 53
*
Corresponding authors.
E-mail addresses: yrao@mail.tsinghua.edu.cn (Y. Rao), zh19683@163.com
(H. Zhang).
1
These authors contribute equally to this work.
http://dx.doi.org/10.1016/j.cclet.2015.07.011
1001-8417/ß 2015 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article in press as: G. Shan, et al., Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.07.011

G Model
CCLET 3388 1–5
2
G. Shan et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
layer was separated, dried over anhydrous Na2SO4 and concen-
69
trated on rotavapor under reduced pressure. Finally the residue
was purified by silical gel column chromatography to give
corresponding products.
70
71
72
73
2-(Chlorophenyl)(phenyl)methanone (1b): 1H NMR (400 MHz,
CDCl3):
d
7.83–7.81 (m, 2H), 7.60 (t, 1H, J = 7.6 Hz), 7.49–7.42 (m,
195.4, 138.8,
74
75
4H), 7.39–7.37 (m, 2H); 13C NMR (100 MHz, CDCl3):
d
136.7, 133.8, 131.5, 131.2, 130.2, 129.3, 128.8, 126.8; LRMS (ESI)
calcd. for C13H10ClO [M+H]+: 217.03, found 217.03.
76
77
1-(2-Chloro-4-methylphenyl)-2,2-dimethylpropan-1-one (2b):
78
79
80
1H NMR (400 MHz, CDCl3):
d
7.21 (s, 1H), 7.06 (d, 1H, J = 7.96 Hz),
7.02 (d, 1H, J = 7.76 Hz), 2.34 (s, 3H), 1.25 (s, 9H); 13C NMR
(100 MHz, CDCl3):
d
211.9, 140.2, 137.8, 130.4, 129.4, 127.0, 126.1,
81
82
83
45.3, 27.0, 21.1; LRMS (ESI) calcd. for C12H16ClO [M+H]+: 271.08,
found 271.25.
1-(2-Chloro-4-fluorophenyl)-2,2-dimethylpropan-1-one
84
85
86
(3b): 1H NMR (400 MHz, CDCl3):
d
7.17–7.12 (m, 2H), 7.02–6.98
(m, 1H), 1.26 (s, 9H); 13C NMR (100 MHz, CDCl3):
d
210.9, 162.4 (d,
J = 250 Hz), 136.7 (d, J = 4.05 Hz), 130.9 (d, J = 10.17 Hz), 127.5 (d,
J = 8.93 Hz), 117.6 (d, J = 24.46 Hz), 113.8 (d, J = 21.48 Hz), 45.5,
27.0; LRMS (ESI) calcd. for C11H13ClFO [M+H]+: 215.06, found
215.28.
87
88
89
90
Scheme 1. Different approaches for the synthesis of 2-chloro aromatic ketones.
1-(2,4-Dichlorophenyl)-2,2-dimethylpropan-1-one (4b): 1H
91
NMR (400 MHz, CDCl3):
d
7.42 (d, 1H, J = 1.7 Hz), 7.28–7.26 (m,
92
93
1H), 7.09 (d, 1H, J = 8.2 Hz), 1.26 (s, 1H); 13C NMR (100 MHz,
54
55
56
57
58
59
yields (entry 9). DCE was proved to be the better solvent. Other
solvents, such PhMe, only gave 10% 1H-NMR yield (entry 10). The
reaction could also proceed at 60 8C with a slightly lower 1H NMR
yield (entry 12). In general, the reaction will proceed to completion
with 10 mol% Pd(OAc)2, 1.0 equiv. of TfOH, 1.05 equiv. of NCS,
1.05 equiv. of K2S2O8 in DCE within 10 h at 80 8C.
CDCl3):
d
210.7, 139.0, 135.2, 130.7, 130.0, 127.2, 126.8, 45.4, 27.0;
94
95
96
97
98
99
LRMS (ESI) calcd. for C11H13Cl2O [M+H]+: 231.03, found 231.98.
1-(4-Bromo-2-chlorophenyl)-2,2-dimethylpropan-1-one (5b):
1H NMR (400 MHz, CDCl3):
d
7.58 (d, 1H, J = 1.68 Hz), 7.41 (dd, 1H,
J = 1.72 Hz, J = 8.14 Hz), 7.02 (d, 1H, J = 8.16 Hz), 1.25 (s, 1H); 13C
NMR (100 MHz, CDCl3):
d
210.6, 139.5, 132.8, 130.8, 129.6, 127.4,
122.9, 45.4, 26.9; LRMS (ESI) calcd. for C11H13BrClO [M+H]+:
274.98, found 274.12.
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
60
2.2. General procedure for the C–H chlorination
1-(2-Chloro-4-methoxyphenyl)-2,2-dimethylpropan-1-one
61
62
63
64
65
66
67
68
Aromatic ketones (0.2 mmol, 1.0 equiv.), NCS (0.21 mmol,
1.05 equiv.), Pd(OAc)2 (0.01 mmol, 0.05 equiv.) and K2S2O8
(0.21 mmol, 1.05 equiv.) were dissolved in commercially available
dichloroethane (1 mL). Then TfOH (0.2 mmol, 1.0 equiv.) was
added into the reaction solution. The reaction mixture was stirred
at 80 8C for 3–30 h. After completion of the reaction, the mixture
was cooled to room temperature and then saturated NaHCO3
aqueous solution was added to quench the reaction. The organic
(6b): 1H NMR (400 MHz, CDCl3):
d
7.07 (d, 1H, J = 8.36 Hz), 6.92 (s,
1H), 6.79 (d, 1H, J = 7.88 Hz), 3.18 (s, 3H), 1.25 (s, 9H); 13C NMR
(100 MHz, CDCl3): d 211.3, 160.1, 132.9, 130.6, 127.0, 115.2, 112.2,
55.6, 45.3, 27.0; LRMS (ESI) calcd. for C19H24ClO [M+H]+:227.08,
found 227.96.
Adamantan-1-yl(2-chloro-3,5-dimethylphenyl)methanone
(7b): 1H NMR (400 MHz, CDCl3):
d
7.04 (s, 1H), 6.72 (s, 1H), 2.34 (s,
3H), 2.30 (s, 3H), 2.04 (s, 3H), 1.95 (m, 6H), 1.75–1.68 (m, 3H); 13
NMR (100 MHz, CDCl3): 211.8, 140.5, 136.8, 136.0, 131.7, 126.3,
C
d
124.4, 47.3, 38.5, 36.6, 28.1, 21.0, 20.2; LRMS (ESI) calcd. for
12H16ClO2 [M+H]+: 303.14, found 303.05.
Table 1
C
Optimization of reaction conditions.
Adamantan-1-yl(2-chloro-4-methylphenyl)methanone (8b):
Cl
O
H
O
1H NMR (400 MHz, CDCl3):
d
7.20 (s, 1H), 7.06 (d, 1H,
J = 7.72 Hz), 6.99 (d, 1H, J = 7.72 Hz), 2.34 (s, 3H), 2.04 (s, 3H),
1.94 (m, 6H), 1.75–1.66 (m, 6H); 13C NMR (100 MHz, CDCl3):
Conditions
10 h
d
(1b)
211.0, 140.0, 137.3, 130.2, 129.3, 126.8, 126.2, 47.4, 38.3, 36.4, 27.9,
21.0; LRMS (ESI) calcd. for C18H22ClO [M+H]+: 289.13, found
289.41.
(1a)
.
Entry
Conditions
Pd(OAc)2, NCS, DCE, 80 8C
Pd(OAc)2, NCS, AcOH, DCE, 80 8C
Pd(OAc)2, NCS, TFA, DCE, 80 8C
Yield (%)a
Adamantan-1-yl(2-chloro-5-methylphenyl)methanone (9b):
1H NMR (400 MHz, CDCl3):
d
7.26–7.24 (m, 1H), 7.09 (d, 1H,
J = 8.12 Hz), 6.89 (s, 1H), 2.34 (s, 3H), 2.04 (s, 3H), 1.95–1.94 (d, 6H,
J = 2.08 Hz), 1.72–1.71 (m, 6H); 13C NMR (100 MHz, CDCl3):
1
2
NR
NR
NR
85
3
d
4
Pd(OAc)2, NCS, TfOH, DCE, 80 8C
211.3, 140.2, 136.3, 130.5, 129.6, 126.9, 126.4, 47.4, 38.4, 36.6, 28.1,
21.1; LRMS (ESI) calcd. for C18H22ClO [M+H]+: 289.13, found
289.07.
5
Pd(OAc)2, NCS, TfOH, Na2S2O8, DCE, 80 8C
Pd(OAc)2, NCS, TfOH, K2S2O8, DCE, 80 8C
Pd(OAc)2, NCS, TfOH, (NH4)2S2O8, DCE, 80 8C
NCS, TfOH, K2S2O8, DCE, 80 8C
Pd(MeCN)Cl2, NCS, TfOH, K2S2O8, DCE, 80 8C
Pd(OAc)2, NCS, TfOH, K2S2O8, PhMe, 80 8C
Pd(OAc)2, NCS, TfOH, K2S2O8, DCE, 100 8C
Pd(OAc)2, NCS, TfOH, K2S2O8, DCE, 60 8C
90
6
96(83)b
85
7
8
NR
38
9
2.3. General procedure for the preparation of 3-
128
129
10
11
12
10
phenylbenzo[d]isoxazole (11)
93
78
A mixture of aromatic ketone (1b, 216 mg, 1 mmol, 1.0 equiv.),
hydroxylamine hydrochloride (83.4 mg, 1.2 mmol, 1.2 equiv.)
and sodium acetate trihydrate (163.3 mg, 1.2 mmol, 1.2 equiv.)
130
131
132
DCE(1,2-dichloroethane); TfOH(trifluoromethansulfonic acid).
a
NMR yield using 4-nitrobenzaldehyde as internal standard.
b
Isolated yield.
Please cite this article in press as: G. Shan, et al., Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.07.011

G Model
CCLET 3388 1–5
G. Shan et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
3
Table 2
Substrates scope for C–H chlorination of aromatic ketones.
Cl
O
H
O
5 mol%Pd(OAc)2, 1.05 equiv. K2S2O8,
1.05 equiv. NCS, 1.0 equiv. TfOH,
R2
R2
R1
R1
DCE, 80 o
C
.
Entry
Reagent
Time (h)
12
Product
Cl
Yield (%)
87
1
2
O
O
Me
Me
2b
2a
25
30
28
61
87
77
O
Cl
O
F
F
3a
3b
Cl
3
4
O
O
O
Cl
Cl
Br
4b
Cl
4a
5a
O
Br
5b
5
6
3.7
3.7
58
93
Cl
O
O
MeO
Me
MeO
Me
6a
6b
Cl
O
O
Me
Me
Cl
7a
7b
7
8
12
17
94
90
O
O
Me
Cl
Me
8b
8a
O
O
Me
Cl
Me
9b
9a
O
9
8
0
O
Me
Me
10a
10b
133
134
135
136
137
138
139
140
141
dissolved in ethanol (5 mL) were refluxed for 24 h under Ar
atmosphere. H2O was added to the mixture and the reaction
mixture was extracted by ethyl acetate (8 mL 3 times). The
combined organic phase was washed with brine and dried over
Na2SO4. The solvent was evaporated and the residue was purified
by silica gel column chromatography to give intermediate product
(196.4 mg, 85%).
for 10 h. H2O was added to the mixture and the reaction mixture 142
was extracted by ethyl acetate (8 mL Â 3). The combined organic 143
phase was washed with brine and dried over Na2SO4. The solvent 144
was evaporated and the residue was purified by silica gel column 145
chromatography to give product (11, 17.6 mg, 88%). 1H NMR 146
(400 MHz, CDCl3):
7.37 (m, 1H); 13C NMR (100 MHz, CDCl3):
129.9, 129.3, 129.1, 128.2, 124.0, 122.4, 120.6; LRMS (ESI) calcd. for 149
C13H10NO [M+H]+: 196.07, found 196.04.
150
d
7.99–7.93 (m, 3H), 7.67–7.54 (m, 5H), 7.40– 147
d
164.0, 157.4, 130.4, 148
A mixture of intermediate (21.4 mg, 0.1 mmol, 1.0 equiv.) and t-
BuOK (22.4 mg, 0.2 mmol, 2.0 equiv.) in THF (3 mL) was refluxed
Please cite this article in press as: G. Shan, et al., Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.07.011

G Model
CCLET 3388 1–5
4
G. Shan et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
Scheme 2. Applications in heterocycle synthesis. Conditions: (a) 2 equiv. NH2OHÁHCl, EtOH, reflux; (b) 2 equiv. t-BuOK, THF, reflux; (c) 5.1 equiv AcCl, 1 equiv. Ts-NHNH2,
EtOH, reflux (d) 0.1 equiv. PdCl2(dppf)ÁDCM, 2 equiv. t-BuOK, dioxane, 80 8C.
151
152
2.4. General procedure for the preparation of 3-phenyl-1-tosyl-1H-
noted that air- or moisture-proof operations were not essential for
this reaction.
202
203
204
205
206
207
208
209
210
211
212
213
214
215
indazole (12)
To further exemplify the synthetic utility of this chlorination
reaction, two biologically important heterocyclic compounds
were selected as synthetic targets. Compound (11) has fungi-
static activity against Pestalotia annonicola [8]. Indazole
derivatives are also important compounds in medicinal chemis-
try fields [9]. As shown in Scheme 2, derivatives of benzo[d]i-
soxazole and 1H-indazole were readily prepared from the
chlorination compound (1b) in satisfactory yields by a nucleo-
philic addition and cyclization sequence [1,10]. Additionally this
method should be potentially used to late-stage modification of
drugs with aryl ketone scaffold, such as Ketoprofen and
Fenofibrate.
153
154
155
156
157
158
159
160
161
162
163
164
165
166
167
168
169
170
171
172
173
174
175
176
177
178
179
180
181
182
183
184
Acetyl chloride (0.4 g, 0.36 mL, 5.1 mmol, 5.1 equiv.) was added
slowly to 4 mL EtOH at 0 8C. Stirring was continued for 30 min at
room temperature. (2-Chlorophenyl)(phenyl)methanone (1b,
1.0 mmol, 1.0 equiv.) was dissolved in ethanol (6 mL) and added
to acidic EtOH-solution followed by addition of p-toluenesulfo-
nylhydrazide (0.48 g, 2.6 mmol, 2.6 equiv.). The reaction was
stirred overnight (18 h) at room temperature. The reaction was
monitored by TLC. When the reaction completed, the reaction
mixture was poured into water (10 mL). The obtained mixture was
rotary evaporated until the complete removal of EtOH. The residue
was extracted by EtOAc (8 mL Â 3). The reactions were monitored
by TLC, wherein the mixture was poured into water and the
aqueous solution extracted with EtOAc. Combined organic layer
was washed with water (20 mL) and brine (20 mL), dried over
Na2SO4, filtered and concentrated on rotavapor under reduced
pressure. Finally the residue was purified by silical gel column
chromatography to give corresponding intermediate product
(30.7 mg, 80%).
4. Conclusion
216
In summary, a convenient and efficient method for the
preparation of 2-chloro aromatic ketones was developed. Chlorine
atom was successfully introduced on the ketone molecules
through palladium-catalyzed ortho-selective C(sp2)–H chlorina-
tion. This efficient approach toward 2-chloro aromatic ketones
paved the way for the synthesis of various heterocycles. Moreover,
this chlorination reaction had the potential for late-stage
modification of drug candidates and rapid access of drug analogs.
217
218
219
220
221
222
223
224
A
mixture of intermediate (38.4 mg, 0.1 mmol, 1 equiv.),
PdCl2(dppf)ÁDCM (8.16 mg, 0.01 mmol, 0.1 equiv.), and t-BuOK
(22.4 mg, 0.2 mmol, 2 equiv.) dissolved in dioxane (3 mL) was
stirred at 80 8C for 6 h under Ar atmosphere. The reaction mixture
was filtered through a pad of Celite and the filtrate was evaporated.
The residue was purified by silica gel column chromatography
eluting with hexane-ethyl acetate (8:1) to give product (12,
Acknowledgments
225
29.6 mg, 85%). 1H NMR (400 MHz, CDCl3):
d 8.27 (d, 1 H,
This work was supported by ‘973’ grant (No. 2011CB965300), Q2 226
J = 8.48 Hz), 7.94–7.90 (m, 5H), 7.58 (t, 1H, J = 7.68 Hz), 7.52–
7.47 (m, 3H), 7.37 (t, 1H, J = 7.68 Hz), 7.24 (t, 3H, J = 8.12 Hz), 2.34
NSFC (No. 21142008, 21302106), Tsinghua University 985 Phase II
funds and the Tsinghua University Initiative Scientific Research
Program.
227
228
229
(s, 3H); 13C NMR (100 MHz, CDCl3):
d 151.8, 145.4, 142.0, 134.8,
131.6, 129.9, 129.7, 129.2, 129.0, 128.4, 127.8, 124.6, 124.5, 121.8,
113.8, 21.8; LRMS (ESI) calcd. for C20H17N2O2S [M+H]+: 349.09,
found 349.00.
References
230
[1] (a) A.Y. Solovyev, D.A. Androsov, D.C. Neckers, One-pot synthesis of substituted 2-
aminobenzo[b]thiophenes, J. Org. Chem. 72 (2007) 3122–3124;
(b) Q. Cai, Z.Q. Li, J.J. Wei, et al., Assembly of indole-2-carboxylic acid esters
through a ligand-free copper-catalysed cascade process, Chem. Commun. (2009)
7581–7583;
231
232
233
234
235
236
237
238
239
240
241
242
243
244
245
246
247
248
249
250
251
252
253
254
255
185
3. Results and discussion
186
187
188
189
190
191
192
193
194
195
196
197
198
199
200
201
With the optimized conditions in hand, we began to study the
substrates scope of this chlorination reaction. As displayed in
Table 2, a variety of ketones were smoothly transformed into the
corresponding 2-chloro aromatic ketones in good to excellent
yields. To examine the functional groups tolerance of this reaction,
a series of ketones with para-methyl, F, Cl, Br, and methoxyl
groups, was prepared and examined (2a–6a). The results showed
that this reaction could tolerate with either electron-donating
functional groups (methyl and methoxyl group) or electron-
withdrawing functional groups (F, Cl and Br). To further study the
influence of substitution patterns to the reactivity, several ketones
with para, meta, and ortho-methyl group, were tested (7a–10a).
Both para and meta-methyl substituted ketones gave satisfactory
yields (7b–9b). However, there was no reaction at all for ortho-
methyl substituted ketone (10b), possibly due to the large steric
hindrance between adamantly and methyl groups. It should be
(c) L.B. Fu, X.L. Huang, D.P. Wang, P.H. Zhao, K. Ding, Copper(I) iodide catalyzed
synthesis of quinolinones via cascade reactions of 2-halobenzocarbonyls with 2-
arylacetamides, Synthesis 10 (2011) 1547–1554;
(d) K. Inamoto, M. Katsuno, T. Yoshino, et al., Synthesis of 3-substituted indazoles
and benzoisoxazoles via Pd-catalyzed cyclization reactions: application to the
synthesis of nigellicine, Tetrahedron 63 (2007) 2695–2711.
[2] K. Naumann, Influence of chlorine substituents on biological activity of chemicals:
a review, Pest Manag. Sci. 56 (2000) 3–21.
[3] (a) R. Parella, A. Kumar Naveen, S.A. Babu, Catalytic Friedel–Crafts acylation:
magnetic nanopowder CuFe2O4 as an efficient and magnetically separable cata-
lyst, Tetrahedron Lett. 54 (2013) 1738–1742;
(b) E. Berliner, The influence of n-alkyl groups on the rate of a cyclization reaction,
J. Am. Chem. Soc. 66 (1944) 533–535;
(c) A.P. Huang, X.Y. Liu, L.H. Li, et al., Antimony(V) chloride-benzyltriethylam-
monium chloride complex as an efficient catalyst for Friedel–Crafts acylation
reactions, Adv. Synth. Catal. 346 (2004) 599–602;
(d) M.S. Gowda, S.S. Pande, R.A. Ramakrishna, K.R. Prabhu, Acylation of Grignard
reagents mediated by N-methylpyrrolidone: a remarkable selectivity for the
synthesis of ketones, Org. Biomol. Chem. 9 (2011) 5365–5368;
(e) C. Hyun-Hee, K. Seung-Hoi, A versatile protocol for the preparation of highly
Please cite this article in press as: G. Shan, et al., Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.07.011

G Model
CCLET 3388 1–5
G. Shan et al. / Chinese Chemical Letters xxx (2015) xxx–xxx
5
256
257
258
259
260
261
262
263
264
265
266
267
268
269
270
271
272
273
274
275
276
277
278
279
280
281
282
283
284
hindered aryl ketones using organozinc reagents, Bull. Korean Chem. Soc. 33 relative directing-group abilities, Angew. Chem. Int. Ed. 52 (2013) 4440–4444;
285
(2012) 3083–3086.
(b) X.Y. Sun, Y.H. Sun, C. Zhang, Y. Rao, Room-temperature Pd-catalyzed C–H 286
chlorination by weak coordination: one-pot synthesis of 2-chlorophenols with 287
[4] (a) W. Zeng, T.E. Ballard, A.G. Tkachenko, et al., Mimicking the biological activity
of diazobenzo[b]fluorene natural products with electronically tuned diazofluor-
ene analogs, Bioorg. Med. Chem. Lett. 16 (2006) 5148–5151;
excellent regioselectivity, Chem. Commun. 50 (2014) 1262–1264.
288
[7] (a) K.M. Engle, T.S. Mei, M. Wasa, J.Q. Yu, Weak coordination as powerful means 289
for developing broadly useful C–H functionalization reactions, Acc. Chem. Res. 45 290
(b) I.D. Ivanchikova, N.I. Lebedev, M.S. Shvartsberg, A simple synthesis of angular
anthrathiophenediones via acetylenic derivatives of anthraquinone, Synthesis 13
(2004) 2131–2134;
(c) C.H. Park, D.R. Brittelli, C.L. Wang, F.D. Marsh, W.A. Gregory, M.A. Wuonola, R.J.
McRipley, V.S. Eberly, A.M. Slee, M. Forbes, Antibacterials. Synthesis and struc-
ture–activity studies of 3-aryl-2-oxooxazolidines. 4. Multiply-substituted aryl
derivatives, J. Med. Chem. 35 (1992) 1156–1165.
(2012) 788–802;
291
(b) T.S. Mei, R. Giri, N. Maugel, J.Q. Yu, Pd-catalyzed mono-selective ortho- 292
halogenation of C–H bonds assisted by counter cations: an orthogonal method 293
to directed ortho-lithiation, Angew. Chem. Int. Ed. 47 (2008) 5215–5219;
(c) Q.Z. Zheng, N. Jiao, Transition-metal-catalyzed ketone-directed ortho-C–H 295
functionalization reactions, Tetrahedron Lett. 55 (2014) 1121–1126;
(d) L.H. Wang, L. Ackermann, Ruthenium-catalyzed ortho-C–H halogenations of 297
benzamides, Chem. Commun. 55 (2014) 1083–1085;
294
296
298
[5] (a) D. Kalyani, A.R. Dick, W.Q. Anani, M.S. Sanford, A simple catalytic method for
the regioselective halogenation of arenes, Org. Lett. 8 (2006) 2523–2526;
(b) C. Lu, S.Y. Zhang, G. He, W.A. Nack, G. Chen, Palladium-catalyzed picolina-
mide-directed halogenation of ortho C–H bonds of benzylamine substrates,
Tetrahedron 70 (2014) 4197–4203;
(e) S. Ma, G. Villa, P.S. Thuy-Boun, A. Homa, J.Q. Yu, Pd-catalyzed ortho-selective 299
C–H deuteration of arenes, evidence for superior reactivity of weakly coordinated 300
palladacycles, Angew. Chem. Int. Ed. 53 (2014) 734–737.
301
(c) X.Y. Sun, Y.H. Sun, Y. Rao, A gram-scale synthesis of multi-substituted arenes
via palladium catalyzed C–H halogenation, Chin. Chem. Lett. 25 (2014) 667–669;
(d) B.C. Chary, S. Kim, Rhodium(III)-catalyzed ortho-olefination of aryl phospho-
nates, Org. Biomol. Chem. 11 (2013) 6879–6882;
(e) N. Schro¨der, J. Wencel-Delord, F. Glorius, High-yielding, versatile, and practi-
cal [Rh(III)Cp*]-catalyzed ortho-bromination and iodination of arenes, J. Am.
Chem. Soc. 134 (2012) 8298–8301;
(f) G. Shan, X. Yang, L. Ma, Y. Rao, Pd-catalyzed C–H oxygenation with TFA/TFAA:
expedient access to oxygen-containing heterocycles and late-stage drug modifi-
cation, Angew. Chem. Int. Ed. 51 (2012) 13070–13074.
[8] B.M. Bhawal, D.S. Mukadam, K.A. Thakar, Pesticidal activity of some 1,2-benzi- 302
soxazole derivatives, Marathwada Univ. J. Sci. Nat. Sci. 17 (1978) 21–22.
303
[9] (a) X. Wang, S.X. Wang, Y.T. Liu, et al., Comparative effects of SNX-7081 and SNX- 304
2112 on cell cycle, apoptosis and Hsp90 client proteins in human cancer cells, 305
Oncol. Rep. 33 (2015) 230–238;
306
(b) S. Moon, M. Hanif, M. Kubanik, et al., organoruthenium and osmium antican- 307
cer complexes bearing a maleimide functional group: reactivity to cysteine, 308
stability, and cytotoxicity, ChemPlusChem 80 (2015) 231–236.
309
[10] Y. Xia, F.D. Hu, Z.X. Liu, et al., Palladium-catalyzed diarylmethyl C(sp3)–C(sp2) 310
bond formation: a new coupling approach toward triarylmethanes, Org. Lett. 15 311
[6] (a) X.Y. Sun, G. Shan, Y.H. Sun, Y. Rao, Regio- and chemoselective C–H chorina-
tion/bromination of electron deficient arenes by weak coordination and study of
(2013) 1784–1787.
312
Please cite this article in press as: G. Shan, et al., Palladium-catalyzed ortho-selective C–H bond chlorination of aromatic ketones, Chin.
Chem. Lett. (2015), http://dx.doi.org/10.1016/j.cclet.2015.07.011