A gram-scale synthesis of multi-substituted arenes via palladium catalyzed C-H halogenation

Article abstract of DOI:10.1016/j.cclet.2014.03.021

(6-Amino-2-chloro-3-fluorophenyl)methanol is prepared through both traditional methods and palladium catalyzed iterative C-H halogenation reactions. In comparison to traditional approach, the C-H functionalization strategy demonstrated a few advantages in

Full text of DOI:10.1016/j.cclet.2014.03.021

Chinese Chemical Letters 25 (2014) 667–669
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Original article
A gram-scale synthesis of multi-substituted arenes via palladium
catalyzed C–H halogenation
*
Xiu-Yun Sun, Yong-Hui Sun, Yu Rao
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:
(6-Amino-2-chloro-3-fluorophenyl)methanol is prepared through both traditional methods and
palladium catalyzed iterative C–H halogenation reactions. In comparison to traditional approach, the
C–H functionalization strategy demonstrated a few advantages including milder reaction conditions,
higher yields, better selectivity and practicality, and high chemical diversity.
Received 15 January 2014
Received in revised form 17 February 2014
Accepted 27 February 2014
Available online 14 March 2014
ß 2014 Yu Rao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
Keywords:
Palladium catalysis
C–H halogenation
Substituted arenes
1. Introduction
demonstrated in an iterative ortho-halogenation reaction and
large-scale synthesis of some simple aryl halides. Here, we report a
Aromatic halides are an important class of chemicals which has
been extensively used in modern organic syntheses and pharma-
ceutical industry [1]. Currently the most prevalent approaches to
access aromatic halides still highly rely on the classic protocols [2],
such as eletrophilic aromatic substitution, directed ortho-lithiation
and Sandmeyer reaction, etc. However, those methodologies
always suffer from one or more limitations including harsh
reaction conditions, poor regioselectivity, moisture sensitivity, low
yield, and tedious reaction operations, etc. In recent years,
transition metals catalyzed C–H functionalization reactions
through weak coordination had emerged as powerful tools for
aromatic carbon-halide bond formation [3]. For example, this
strategy has been successfully applied to prepare aromatic iodides
with substrates, such as phenyl acetic acids, benzoic acids, and
sulfonamides by palladium catalysis.
synthetic study of the gram-scale synthesis of multi-substituted
aryl halides through both palladium catalyzed C–H halogenation
reactions and traditional methods respectively. The aryl halides
can be further transformed into (6-amino-2-chloro-3-fluorophe-
nyl)methanol, which is a useful synthetic intermediate employed
in medicinal chemistry and organic electronic material. For
example, this compound will serve as a basic building block for
the OLED (organic light-emitting diode) material synthesis. A brief
comparison between these two strategies was summarized to
highlight the advantages of our new C–H halogenation method.
2. Experimental
2.1. Synthesis of compounds 2–5 via C–H activation approach
More recently, we developed a palladium(II)-catalyzed ortho-
halogenation reaction to prepare a variety of arene halides with
electron-deficient arenes and NBS/NCS [4]. In our studies, ester
groups were found to work as an effective directing group for
promoting ortho C–H activation and this protocol can be conducted
in mild conditions without the need for moisture- or air-proof
conditions. The efficiency and utility of this method has also been
Ethyl 2-bromo-5-fluorobenzoate (2): Compound 1 (1.68 g,
1.0 equiv.), NBS (1.87 g, 1.05 equiv.), Pd(OAc)2 (78.5 mg,
0.035 equiv.) and Na2S2O8 (2.86 g, 1.2 equiv.) were dissolved in
commercial dichloroethane (12 mL) in a 100 mL round bottom
flask. Then TfOH (2.2 mL, 2.5 equiv.) was added into the reaction
solution. Then the reaction mixture was stirred at 80 8C for 9 h.
After completion of the reaction, the mixture was cooled to room
temperature and then saturated NaHCO3 was added to quench the
reaction. The reaction mixture was diluted with dichloromethane
and washed once with saturated aqueous NaHCO3. Then organic
layer was dried over Na2SO4 and concentrated on rotavapor under
*
Corresponding author.
E-mail address: yrao@mail.tsinghua.edu.cn (Y. Rao).
1001-8417/$ – see front matter ß 2014 Yu Rao. Published by Elsevier B.V. on behalf of Chinese Chemical Society. All rights reserved.
http://dx.doi.org/10.1016/j.cclet.2014.03.021

668
X.-Y. Sun et al. / Chinese Chemical Letters 25 (2014) 667–669
reduced pressure. Finally the residue was purified by silical gel
column chromatography to give compound 2 (1.71 g) in 70% yield.
Ethyl 6-bromo-2-chloro-3-fluorobenzoate (3): Compound 3
was prepared with similar procedure as compound 2. Compound 2
(1.45 g, 1.0 equiv.), NCS (0.83 g, 1.05 equiv.), Pd(OAc)2 (52.9 mg,
0.04 equiv.), Na2S2O8 (1.68 g, 1.2 equiv.), TfOH (2.6 mL, 5.0 equiv.)
were used. The reaction mixture was stirred at 80 8C for 4 h. Finally,
compound 3 (0.78 g) was obtained in 47% yield.
Ethyl 6-amino-2-chloro-3-fluorobenzoate (4): Compound 3
(560 mg, 1.0 equiv.), Cu2O (28.6 mg, 0.1 equiv.), ammonium
hydroxide (25%) (3.1 mL, 10.0 equiv.) were dissolved in NMP
(5 mL) in a sealed tube. The reaction mixture was stirred at 80 8C
for 12 h. With similar workup as above, finally, compound 4
(390 mg) was obtained in 90% yield.
vacuo. Finally the crude was purified by silical gel column
chromatography to give the compound 5 (458 mg) in a yield of
76%.
3. Results and discussion
At the beginning of our synthetic studies towards (6-amino-2-
chloro-3-fluorophenyl)methanol, we envisioned two halide atoms
can be introduced into both ortho-positions (2- and 6-) of 3-
fluorobenzoates through weak coordination assisted C–H haloge-
nation.
A following aminolysis manipulation can selectively
transform the 6-halide group into an amino functional group. As
depicted in Scheme 1, we started our investigation with our newly
developed iterative C–H halogenation methods. Starting with a
simple ethyl 3-fluorobenzoate, brominated product 2 can be
smoothly produced via the first C–H bromination on a gram scale
in 70% yield. Then, a second C–H chlorination reaction was
conducted under the optimum reaction conditions. We were
(6-Amino-2-chloro-3-fluorophenyl)methanol
(5):
LiAlH4
(50 mg, 2.2 equiv.) in anhydrous THF (1.32 mL) was added
dropwise to compound 4 (130 mg, 1.0 equiv.) in anhydrous THF
(4 mL) at 0 8C. Then the mixture was added at room temperature
for 6 h. Finally compound 5 (63 mg) was obtained in 60% yield.
pleased to find that dihalogenated intermediate
3 can be
successfully obtained in a yield of 47% on a gram scale with an
excellent regioselectivity. It is noteworthy to point out that the
second chlorination reaction is quite challenging because of the
intrinsic electron-poor property and high steric hindrance of
compound 2 from the first bromination step. The amount of TfOH
was a key factor for C–H halogenations. 2.5 equiv. of TfOH was
sufficient to promote the reaction in the bromination step.
However, more TfOH (5.0 equiv.) was needed in the second
chlorination step, which might be due to the electron-deficiency of
arene 2. With the compound 3 in hand, we conducted aminolysis to
selectively replace bromine atom into amino group, which can
readily give intermediate 4 in an excellent yield (90%) [5]. A
reduction with lithium aluminium hydride can finally furnish
desired product 5 in a good yield of 60% [6]. The overall yield was
18% in four steps. As shown in Scheme 2, a synthetic comparison
study of compound 5 with classical methods was also conducted in
parallel. With 3-fluorobenzoic acid 6 as the starting material, this
2.2. Synthesis of compounds of 7–5 via traditional approach
2-Chloro-3-fluorobenzoic acid (7): A solution of 3-fluoroben-
zoic acid (6, 4.02 g, 1.0 equiv.) in 20 mL of THF was added dropwise
to a suspension of TMEDA (10.0 mL, 2.3 equiv.) and 1.5 mol/L n-
BuLi (42.1 mL, 2.2 equiv.) in 50 mL of THF at ꢀ78 8C. The mixture
was stirred at ꢀ78 8C for 30 min, and then
a solution of
hexachloroethane (2.72 g, 4.0 equiv.) in 50 mL of THF was added.
After 12 h, the reaction was quenched with water and diluted with
diethyl ether. The bilayer was adjusted to pH 1–2 with conc.
hydrochloric acid. The organic layer was washed with water, brine,
dried and concentrated to give crude as a tan solid, which was
washed with hexane to give of the desired product 7 (3.0 g) in 60%
yield.
2-Chloro-3-fluoro-6-nitrobenzoic acid (8): In a three necked
flask fitted with a dropping funnel and a thermometer were
charged compound 7 (5 g, 1.0 equiv.) and concentrated H2SO4
(43 mL). After cooling to 0 8C, HNO3 (70%, 3.3 mL) was added
dropwise over 30 min, keeping the temperature between 0 to
10 8C. After 1 h, the reaction mixture was poured into the crushed
ice keeping the temperature below 20 8C. The mixture was
extracted with EtOAc, the combined extract was washed with
brine and dried over Na2SO4. The filtrate was evaporated to give
mixture (5.35 g) of 8 and 80 (ratio 2:1) and the total yield was 85%.
The mixture was used to synthesize compound 9 directly without
further purification.
(2-Chloro-3-fluoro-6-nitrophenyl)methanol (9): Compound 8
and 80 (2 g, 1.0 equiv.) were dissolved in toluene (10 mL). SOCl2
(1.99 mL, 3.0 equiv.) was then added and the mixture was stirred at
reflux for 3 h under argon. The solvent was evaporated and the
crude chloride was directly reduced. A suspension of NaBH4
(346 mg, 1.0 equiv.) in THF/DMF (15 mL/15 mL, 1:1) under argon
was cooled to 0 8C, then the solution of crude chloride in dry THF
was added dropwise. The mixture was stirred at room temperature
for 24 h. The reaction was quenched by slowly addition of 10% HCl
and extracted with Et2O. The combined organic layer were washed
with brine, dried over Na2SO4 and concentrated. The mixture was
purified by a short column chromatography to give a pure mixture
(1.25 g, ratio 2:1) of compound 9 and 90. The yield for compound 9
determined by 1H NMR was 40% (749 mg).
approach involved ortho-lithiation [7], nitration [8] and
a
sequential reduction [9,10], which can provide product 5 in a
total yield of 10% (4 steps).
In comparison to the synthetic strategy employing C–H
halogenation, based on our experimental results, a few limitations
from traditional methods were summarized as followings: (1) It
was not easy to do the first chlorination reaction with ortho-
lithiation method because of the requirement of absolute
anhydrous conditions and low temperature (ꢀ78 8C) for a long
period of time. Furthermore, safety issue is another concern since a
large amount of strong base (n-BuLi) and toxic hexochloroethane
were used in the reaction. (2) The nitration step using conc. H2SO4
and conc. HNO3 suffered from poor selectivity and gave a mixture
of two regioisomers, which caused a serious purification problem.
(3) The workup of nitro group reduction step was not trivial. As
(6-Amino-2-chloro-3-fluorophenyl)methanol (5): Compound 9
and 90 (1.60 g, 1.0 equiv.), iron powder (2.40 g, 5.5 equiv.) and
NH4Cl (0.30 g, 0.7 equiv.) were suspended in ethanol/water (10:1)
and refluxed for 2 h. The solvent was evaporated and DCM was
added. The mixture was washed with a saturated solution of
sodium carbonate, dried over Na2SO4, filtered and concentrated in
Scheme 1. C–H activation strategy for the synthesis of (6-amino-2-chloro-3-
fluorophenyl)methanol. (a) Pd(OAc)2, NBS, TfOH, Na2S2O8, DCE, 80 8C; (b) Pd(OAc)2,
NCS, TfOH, Na2S2O8, DCE, 80 8C; (c) NH4OH, Cu2O, NMP/H2O, 80 8C; (d) LiAlH4, THF.

X.-Y. Sun et al. / Chinese Chemical Letters 25 (2014) 667–669
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developed to prepare (6-amino-2-chloro-3-fluorophenyl)metha-
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traditional methods, the new strategy employing C–H activation
methods demonstrated a few advantages such as milder reaction
conditions, higher yields, better selectivity and practicality, and
high chemical diversity, etc. As the field of transition metal
catalyzed C–H functionalization keeps moving forward, we expect
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Acknowledgments
This work was supported by ‘973’ Project (No. 2011CB965300),
NSFC (Nos. 21142008, 21302106), Tsinghua University 985 Phase II
Funds and the Tsinghua University Initiative Scientific Research
Program. We thank Prof. L. Liu (Tsinghua University) for helpful
discussions.
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