Metal-free ortho C-H borylation of 2-phenoxypyridines under mild conditions

Article abstract of DOI:10.1021/ol300950r

An efficient metal-free ortho C-H borylation has been developed via sequential borylation of substituted 2-phenoxypyridines with BBr₃ following esterification with pinacol. The corresponding aryl boronates were obtained in good yields. The synt

Full text of DOI:10.1021/ol300950r

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2618–2621
Metal-Free Ortho CÀH Borylation
of 2-Phenoxypyridines under Mild
Conditions
Liting Niu,† Haijun Yang,† Ruji Wang,† and Hua Fu*,†,‡
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology
(Ministry of Education), Department of Chemistry, Tsinghua University, Beijing
100084, P. R. China, and Key Laboratory of Chemical Biology (Guangdong Province),
Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. China
fuhua@mail.tsinghua.edu.cn
Received April 12, 2012
ABSTRACT
An efficient metal-free ortho CÀH borylation has been developed via sequential borylation of substituted 2-phenoxypyridines with BBr3 following
esterification with pinacol. The corresponding aryl boronates were obtained in good yields. The synthesized aryl boronates can be easily
transformed into various useful products. Therefore, the present method makes functionalizations of aryl CÀH bonds easy.
Arylboronic acids and their derivatives are versatile
reagents in modern organic synthesis because they are air
stable and are readily transformed into other desired
products.1 On the other hand, intramolecular complexes
of nitrogen-containing π-conjugated molecules with NÀB
coordination have gained increasing attention from the
viewpoint of development of new π-electron materials.2
Traditional methods for preparation of the boron
compounds use the reactions of either organolithium or
magnesium reagents with boron electrophiles, but they
have a problem with functional-group compatibility. Later,
various alternative approaches to aryl boronates were
developed. Transition-metal-catalyzed, such as Pd-,3 Ni-,4
or Cu-catalyzed,5 borylation of aryl halides is a popular
strategy. Recently, the direct functionalization of unreac-
tive CÀH bonds has emerged as a very active field in
organic synthesis.6 The borylation of arene CÀH bonds
has also been developed under catalysis of transition-metal
catalysts, especially iridium catalysts,7,8 and the iridium-
catalyzed regioselectivity is typically driven by steric
† Department of Chemistry.
‡ Graduate School of Shenzhen.
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r
10.1021/ol300950r
Published on Web 05/01/2012
2012 American Chemical Society

Table 1. Borylation of 2-(p-Tolyloxy)pyridine (1c) with BBr3
and Pinacol to 2-(2-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-
yl)phenoxy)pyridine (3c)a
Figure 1. Our strategy for synthesis of various phenol deriva-
tives through key CÀH borylation.
factors.9 The direct arene borylation by electrophilic sub-
stitution with FriedelÀCrafts chemistry is rare,10 although
the strategy has been reported previously.11 AlCl3 as the
Lewis acid is often required. Since phenol derivatives widely
occur in natural products, biologically active molecules, and
chemical products,12 it is highly desired to develop a prac-
tical and efficient approach to diverse phenol derivatives.
In this paper, we report a novel strategy for synthesis of
phenol derivatives as shown in Figure 1. 2-Phenoxypyr-
idine derivatives are readily prepared via copper-catalyzed
coupling of substituted phenols with pyridines.13 Metal-
free ortho CÀH borylation of 2-phenoxypyridines under
mild conditions leads to 2-phenoxypyridine boronates,
and the aryl boronates are further transformed into var-
ious valuable compounds through cross-coupling and
deprotection of pyridinyl. As shown in Table 1, borylation
of 2-(p-tolyloxy)pyridine (1c) was chosen as the model
reaction. The whole procedure undergoes sequential two-
step couplings: metal-free pyridine-directing CÀH boryla-
tion of 1c gives a 2-(p-tolyloxy)pyridineÀdibromoborane
complex (2c), and esterification of 2c with pinacol provides
2-(4-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-
phenoxy)pyridine (3c). In part A of Table 1, borylation
conditions of 2-(p-tolyloxy)pyridine (1c) with BBr3 was
A. Borylation of 2-(p-Tolyloxy)pyridine (1c) with BBr3
entry
BBr3 (equiv)
base
Et3N
solvent
yieldb (%)
1
2
3
4
5
6
7
8
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (3)
BBr3 (2)
BBr3 (1)
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
dioxane
DMF
75
K2CO3
45
pyridine
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
iPr2NEt
trace
90
55
10
CH2Cl2
CH2Cl2
45
11
B. Borylation of 2-(p-Tolyloxy)pyridine (1c) with BBr3 and Pinacol
Leading to 2-(4-Methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-
2-yl)phenoxy)pyridine (3c)
entry
base
K2CO3
solvent
temp (°C)
yieldc (%)
9
10
11
12
13
14
15
16
17
18
19
20
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
EtOAc
THF
25
25
25
25
25
25
25
25
25
25
0
trace
15
38
40
70
60
10
15
55
18
35
20
K3PO4
pyridine
2,6-lutidine
Et3N
iPr2NEt
Et3N
Et3N
Et3N
CHCl3
CH3CN
CH2Cl2
CH2Cl2
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R. E.; Smith, M. R., III. Science 2002, 295, 305. (c) Ishiyama, T.; Takagi,
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2008, 130, 7534. (e) Robbins, D. W.; Boebel, T. A.; Hartwig, J. F. J. Am.
Et3N
Et3N
Et3N
50
a Reaction conditions: 2-(p-tolyloxy)pyridine (1c) (1 mmol), BBr3
(3 mmol), base (3 mmol), solvent (4 mL) under nitrogen atmosphere.
Reaction time (12 h). b Isolated yield from 1c to 2c. c Isolated yield (total
yield from 1c to 3c).
ꢀ
Chem. Soc. 2010, 132, 4068. (f) Ros, A.; Estepa, B.; Lopez-Rodrıguez,
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Murakami, M. J. Org. Chem. 2010, 75, 8709. (c) Del Grosso, A.;
Singleton, P. J.; Muryn, C. A.; Ingleson, M. J. Angew. Chem., Int. Ed.
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first investigated. We attempted various bases using 3 equiv
of BBr3 as the borylating agent in CH2Cl2 under nitrogen
atmosphere (entries 1À4), and i-Pr2NEt provided the
highest yield (entry 4) (see the Supporting Information
for the workup procedure). Pure 2-(p-tolyloxy)pyridineÀ
dibromoborane complex (2c) was obtained by crystalliza-
tion in CH2Cl2/hexane, and its structure was confirmed by
1H and 13C NMR and EI-MS. Other solvents were also used
(entries 5 and 6), and CH2Cl2 proved to be a suitable solvent
(compare entries 4À6). The amount of BBr3 was changed
(entries 7 and 8), and 3 equiv of BBr3 gave the best result
(entry 4). In order to reduce the loss of 2c during crystal-
lization, we used crude product 2c to optimize conditions of
esterification including bases, solvents, and temperature as
(12) (a) Rappoport, Z. The Chemistry of Phenols; Wiley-VCH: Wein-
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Org. Lett., Vol. 14, No. 10, 2012
2619

Table 2. Borylation of Substituted 2-Phenoxypyridinesa
a Reaction conditions: substituted 2-phenyloxypyridine (1) (1 mmol), BBr3 (3 mmol), i-Pr2NEt (1 mmol), NEt3 (3 mmol), CH2Cl2 (4 mL for two
steps) under nitrogen atmosphere. Reaction time (12 h for borylation; 5À12 h for esterification). b Isolated yield (total yield from 1 to 3).
best result (entry 13). Different reaction temperatures were
attempted (compare entries 13, 19, and 20), and 25 °C was a
suitable temperature.
With these optimized conditions in hand, we investi-
gated the substrate scope of this borylation reaction. As
shown in Table 2, the examined substrates provided good
yields for the sequential two-step process: borylation and
esterification. Arenes with mono- or dimethyl gave yields
between 60 and 89% yield (entries 2À6, 8, 10, 13, and
17À19). Borylation of halogenated (F, Cl, Br, and I) arenes
performed welltogivethe corresponding productsinyields
of 70À86% yield (entries 7À14, 17À20), and the arenes
containing both boronate and halogens provided further
opportunity for synthesis of diverse molecules. A good
yield (72%) was afforded with a naphthalene substrate
(entry 15). The borylation reaction showed high mono-
selectivity, and no diborylated products were observed.
In order to identify structures of the newly synthesized
2-phenoxypyridine boronates (3), we prepared a single
crystal of 3l, and its structure was unambiguously con-
firmed by X-ray diffraction (Figure 2) (see the Supporting
Information for details). The results show a clear NÀB
coordination (distance N(1)ÀB(1) = 1.663(3) A).
Figure 2. Crystal structure of compound 3l.
shown in part B of Table 1 (see the Supporting Information
for details). Various bases were screened in CH2Cl2 under
nitrogen atmosphere (entries 9À14), and NEt3 provided the
highest yield (entry 13). The effect of solvents was investi-
gated (compare entries 13 and 15À18), and CH2Cl2 gave the
2620
Org. Lett., Vol. 14, No. 10, 2012

Scheme 1. Borylation of 1c Leading to 3c on Gram Scale
Scheme 4. Amination of 3c and Deprotection of Pyridyl Group
Scheme 2. Copper-Catalyzed Functionization of 3c under Mild
Conditions
of 3c with 1-iodobenzene yielded 7,18 and easy deprotec-
tion of 7 provided 2-phenylphenol derivative (8) in high
yield according to the reported procedure (Scheme 3).13
We also attempted copper-catalyzed coupling of 3c with
phenylamine via the ChanÀLamÀEvans amination
strategy,8,19 and the amination provided 10 in 60% yield.
Deprotection of the pyridyl group in 10 gave 4-methyl-
2-(phenylamino)phenol (11) using the similar procedure.13
The o-aminophenol derivatives are important intermedi-
ates of biologically active molecules,20 so the present
method is an efficient strategy for the synthesis of
o-aminophenol derivatives (Scheme 4).
Scheme 3. Suzuki Coupling of 3c with 1-Iodobenzene and
Deprotection of Pyridyl Group
In summary, we have developed a simple and efficient
metal-free ortho CÀH borylation of 2-phenoxypyridines.
The borylation protocol uses readily available 2-phenoxy-
pyridines as the starting materials, inexpensive BBr3 as the
borylating reagent, and cheap pinacol as the esterifying agent.
The corresponding aryl boronates were obtained in good
yields. The synthesized aryl boronates are versatile inter-
mediates in modern organic synthesis, and they can be readily
transformed into various useful products. Therefore, the
present method makes functionalizations of phenol-directing
CÀH bonds easy. The convenient and efficient approach will
attract much attention in academic and industrial fields.
Further, we explored the utility of this borylation method.
As shown in Scheme 1, this borylation reaction of 1c on gram
scale worked well under the standard conditions, and the
reaction afforded 3c in 84% yield (Scheme 1). Subsequently,
copper-catalyzed iodination, bromination, and azidonation
of 3c were performed at room temperature according to the
previous methods,14 and the corresponding products con-
taining iodo, bromo, azido groups were obtained in good
yields (Scheme 2). The results showed that the direct CÀH
bond borylation of arenes was particularly valuable.
The 2-arylphenol unitis a keystructural motif15 found in
important natural products, medicinal targets,16 and pri-
vileged ligands.17 We used 2-(4-methyl-2-(4,4,5,5-tetra-
methyl-1,3,2-dioxaborolan-2-yl)phenoxy)pyridine (3c) as
the starting material, palladium-catalyzed Suzuki coupling
Acknowledgment. We thank the National Natural
Science Foundation of China (Grant Nos. 20972083,
21172128, and 21105054) and the Ministry of Science
and Technology of China (Grant No. 2012CB722600)
for financial support
Supporting Information Available. Synthetic proce-
dures, characterization data, X-ray diffraction data for
crystal of compound 3l, and 1H and 13C NMR spectra for
these synthesized compounds. This material is available
free of charge via the Internet at http://pubs.acs.org. The
authors declare no competing financial interest.
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Chem. Rev. 2003, 103, 3155. (b) Brunel, J. M. Chem. Rev. 2005, 105, 857.
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The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 10, 2012
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