Palladium catalyzed ortho-C-H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates

Article abstract of DOI:10.1016/j.tetlet.2015.09.097

A palladium-catalyzed ortho-C-H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates has been developed. The reaction employed the stable and easily accessible hypervalent iodine reagents as both benzoxylate source and oxidant which made the protocol simple and facile. It showed high regioselectivity and good functional group tolerance, and gave the mono-benzoxylation products in moderate to excellent yields.

Full text of DOI:10.1016/j.tetlet.2015.09.097

Accepted Manuscript
Palladium catalyzed ortho-C−H-benzoxylation of 2-arylpyridines using iodo-
benzene dibenzoates
Qian Zhang, Ying Wang, Tingting Yang, Li Li, Dong Li
PII:
S0040-4039(15)30139-8
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.097
TETL 46769
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
12 August 2015
22 September 2015
23 September 2015
Please cite this article as: Zhang, Q., Wang, Y., Yang, T., Li, L., Li, D., Palladium catalyzed ortho-C−H-
benzoxylation of 2-arylpyridines using iodobenzene dibenzoates, Tetrahedron Letters (2015), doi: http://dx.doi.org/
10.1016/j.tetlet.2015.09.097
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−H
Palladium catalyzed ortho-C -benzoxylation of
2-arylpyridines using iodobenzene dibenzoates
Qian Zhang, Ying Wang, Tingting Yang, Li Li, Dong Li
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Palladium catalyzed ortho-C -benzoxylation of 2-arylpyridines using
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iodobenzene dibenzoates
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Qian Zhang,a, b Ying Wang,b Tingting Yang,b Li Li,c Dong Lib, c,
∗
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aHubei Collaborative Innovation Center for High-efficiency Utilization of Solar Energy, Hubei University of Technology, Wuhan
430068, China
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bCollege of Chemistry and Chemical Engineering, Hubei University of Technology, Wuhan 430068, China
cHubei Collaborative Innovation Center of Targeted Antitumor Drug, Jingchu University of Technology, Jingmen 448000, China
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Abstract
A palladium-catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates has been
developed. The reaction employed the stable and easily accessible hypervalent iodine reagents as both benzoxylate
source and oxidant which made the protocol simple and facile. It showed high regioselectivity and good functional
group tolerance, and gave the mono-benzoxylation products in moderate to excellent yields.
Keywords
Palladium catalysis; C–H benzoxylation; Hypervalent iodine reagent
1. Introduction
Transition-metal-catalyzed C–H bond functionalization has become one of the most efficient and facile tools in
organic synthesis, which avoids prefunctionalization of substrates and shows great atom economy.1 Notable progress
has been made predominantly with Pd, Cu, Ru, Rh and Ir for transforming C–H bond to C–C or C–heteroatom
bonds.2 Among them, C–O bond formation especially acyloxylation has attracted considerable attention as the
important role of ester functionality in natural products, pharmaceuticals, and functional materials.3
In 2006, Yu and co-workers reported Cu(II) catalyzed acetoxylation of arene C–H bond in HOAc/Ac2O using
oxygen as oxidant.4 Later Sanford, Kwong, Pelcman, Chen, Liang and Li et al. described the sp2 C–H acetoxylation
of different aromatic substances by using PhI(OAc)2 as acyloxylate source and/or oxidant (Scheme 1, (a)).5 However,
most reports on C–H bond acyloxylation is limited to acetoxylation, the benzoxylation of C–H bond is less
∗ Corresponding author. Tel.: +86-27-59750460; fax: +86-27-59750482; e-mail: dongli@mail.hbut.edu.cn
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developed.6 Aryl benzoates are important as them have been found as key structures of some natural products. A
Rh-catalyzed ortho-benzoxylation of sp2 C–H bond was introduced by Cheng and co-workers in 2009 with benzoic
acids.7 Then, significant efforts have been made towards such ortho-benzoxylation by the groups of Cheng, Patel,
Ackermann and others, employing benzoic acids/salts, benzoyl chlorides, anhydrides, alkylbenzene, benzyl amines,
aryl alkenes or alkynes as benzoxy surrogates and O2, K2S2O8, TBHP or Ag2CO3 as oxidants (Scheme 1, (b)).8 In
general, most of the methods employed independent acyloxylate source and oxidant, which would lead the reaction
condition sophisticated. Otherwise, chemoselectivity remained a problem in these transformations as the mono- and
di-acyloxylation products were usually obtained simultaneously with a non-ignorable ratio. Therefore, it’s highly
desirable to develop simpler and more facile protocols for highly selective C–H bond acyloxylation. In 2013, Wu and
coworkers developed a Pd-catalyzed ortho-benzoxylation of 2-arylpyridines using aryl acylperoxides without
external oxidant.9 Herein, we report the Pd-catalyzed ortho-benzoxylation of 2-arylpyridines using iodobenzene
dibenzoates, a stable hypervalent iodine reagent which was easily accessible from the reaction of PhI(OAc)2 and
benzoic acids,10 as both benzoxylate source and oxidant.
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Scheme 1. Transition-metal-catalyzed ortho-C−H-acyloxylation
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2. Results and discussion
Initial investigation was carried out between 2-phenylpyridine (1a) and iodobenzene dibenzoate (2a) with
Pd(OAc)2 as the catalyst (Table 1). Solvents were first examined. The reaction hardly proceeded in chlorobenzene,
DME and 1,4-dixoane while a mixture of mono- (3a) and di-benzoxylation (4a) products were obtained in CH3CN,
toluene and DCE (Table 1, entries 1–6). The results showed that DCE should be the superior solvent for the reactivity
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but toluene was beneficial for the selectivity. Delighting result was obtained with a mixed solvent of DCE/toluene
(4:1), which greatly promoted the isolated yield ratio of 3a: 4a to 77:9 (Table 1, entry 7). The substrate ratio of
2-phenylpyridine (1a) to iodobenzene dibenzoate (2a) was also essential to the chemoselectivity. With the changing
of substrate ratio from 1:1.3 to 1:1.05, the ratio of 3a: 4a was increased from 77:9 to 85:1 (Table 1, entries 7–10).
Treating the reaction under air caused a slightly decrease of the isolated yield (Table 1, entry 11). Prolonging the
reaction time from 8 h to 12 h didn’t improve the yield of 3a but lead to more conversion to 4a (Table 1, entry 12).
The reaction gave poor yield with lower loading of palladium catalyst and didn’t proceed without catalyst (Table 1,
entry 13, 14). Other palladium catalysts such as PdCl2 and Pd2(dba)3 were not so efficient as Pd(OAc)2 (Table 1, entry
15 and 16). The product yield dramatically decreased under lower temperature (Table 1, entries 17, 18).11
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Table 1. Optimization of the reaction conditionsa
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Entry
Pd(II)
Solvent
T (ºC)
Yield (%)b
1a:2a
3a
˂5
˂5
˂5
50
52
72
77
76
80
85
80
79
38
4a
−
1
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
−
1:1.3
1:1.3
chlorobenzene
DME
130
85
100
85
110
85
85
85
85
85
85
85
85
85
85
85
65
45
−
3
1:1.3
1,4-dioxane
−
4
1:1.3
CH3CN
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7
5
1:1.3
toluene
6
1:1.3
DCE
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9
7
1:1.3
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
DCE/toluene (4:1)
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1:1.2
5
9
1:1.1
4
10
11c
12d
13e
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18
1:1.05
1:1.05
1:1.05
1:1.05
1:1.05
1:1.05
1:1.05
1:1.05
1:1.05
<1
10
<1
2
n.d.
78
−
PdCl2
2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
80
4
60
<1
˂5
−
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aReaction conditions: 2-phenyl pyridine (1a) (0.3 mmol), iodobenzene dibenzoate (2a), palladium
c
catalyst (5 mol%) in solvent (2.0 mL) stirring under N2 for 8 h. bIsolated yield. Reacted for 12 h.
dUnder air. eWith 2.5 mol% Pd(OAc)2.
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Under the optimized conditions, the benzoxylation of a series of 2-arylpyridine (1) with iodobenzene dibenzoate
(2a) were examined as shown in Table 2. Generally, the reaction could tolerate various functional groups such as Me,
OMe, Cl, Br, F, and OCOMe, giving the desired products in good to excellent yields. The 2-arylpyridines which
possessed electron-donating functional groups on the benzene ring gave higher yields than those bearing
electron-withdrawing groups (Table 2, entry 2–7 and 8–14). Especially, isolated product yields of the substrates
possessed an ortho-CH3 or meta-CH3 substituent were up to 99% (Table 2, entry 5–7). Remarkably, the reaction
showed highly regioselectivity when the benzene ring contained a meta-substituted group, in which the benzoxylation
occurred at the sterically less hindered ortho-C–H bond (Table 2, entry 3, 4, 6 and 7). Furthemore, this benzoxylation
could be applied to heteroaryl substrates such as 2-thienyl pyridines, which gave the 3-benzoxylated thiophenes in
good yields (Table 2, entry 15, 16).
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Table 2. The palladium-catalyzed benzoxylation of 2-arylpyridinesa,b
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Entry
Substrate
Product
Yield (%)b
1
68
(1b)
(3b)
2
82
(1c)
(3c)
3
78
(1d)
(3d)
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4
5
6
82
99
99
(1e)
(1f)
(3e)
(3f)
(1g)
(3g)
7
99
(1h)
(1i)
(1j)
(3h)
(3i)
(3j)
(3k)
(3l)
8
9
81
73
57
88
10
11
(1k)
(1l)
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13
14
15
16
76
97
54
83
86
(1m)
(3m)
(3n)
(1n)
(1o)
(1p)
(3o)
O
Ph
O
N
S
(3p)
N
S
(1q)
(3q)
1
2
3
4
aReaction conditions: 2-arylpyridine (1) (0.3 mmol), 2a (0.315 mmol),
Pd(OAc)2 (5 mol%) in DCE/toluene (4:1, 2.0 mL) stirring at 85 ºC
under N2 for 8 h. bIsolated yield.
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The benzoxylation of 2-(3-methyl)phenylpyridine (1g) with various iodobenzene dibenzoate derivatives (2) were
also investigated as shown in Table 3. Good functional group compatibility on the benzoyl group such as Me, OMe, F
and Cl was demonstrated, affording the corresponding desired products in moderate to excellent yields (Table 3, entry
1–4). It was worth noting that the method was also suitable for aliphatic acetoxylation with iodobenzene diacetate
derivetives such as iodobenzene dipivalate, which gave the desired product in 82% yield (Table 3, entry 5).
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Table 3 The palladium-catalyzed acyloxylation of 2-(3-methyl)pyridinesa, b
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Entry
Ar
Product
Yield (%)b
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4-OMe-C6H4
1
54
(2b)
(3r)
(3s)
(3t)
(3u)
(3v)
4-CH3-C6H4
2
91
(2c)
4-F-C6H4
3
4
5
65
53
82
(2d)
4-Cl-C6H4
(2e)
(CH3)3C
(2f)
1
2
3
4
aReaction conditions: 2-arylpyridine (1g) (0.3 mmol), 2 (0.315
mmol), Pd(OAc)2 (5 mol%) in DCE/toluene (4:1, 2.0 mL) stirring
at 85 ºC under N2 for 8 h. bIsolated yield.
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A plausible mechanism for the Pd-catalyzed ortho-benzoxylation of 2-phenylpyridine (1a) with iodobenzene
dibenzoate (2a) was depicted in Scheme 3. Initially, the pyridyl-assisted ortho-C–H activation/cyclopalladation
would occur between Pd(OAc)2 and 2-phenylpyridine (1a) to form a bimetallic Pd(II) complex A. Complex A then
reacted with iodobenzene dibenzoate (2a) to generate the oxidative addition product intermediate B, which might be a
Pd(IV) or bimetallic Pd(III)-Pd(III) complex.6a, 12 Finally, reductive elimination of intermediate B afforded the desired
product 3a and regenerated the palladium(II) species to complete the catalytic cycle.6c, 13
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Scheme 3. Plausible mechanism of the o-benzoxylation
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A control experiment of 2-phenylpyridine with both PhI(OAc)2 and PhI(OBz)2 was also carried out to illustrate
the reaction mechanism (Scheme 4). The result indicated that ortho-benzoxylation was more favored than
ortho-acetoxylation under the standard conditions.
Scheme 4. Control reaction of o-benzoxylation vs o-acetoxylation
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3. Conclusions
In summary, a palladium-catalyzed ortho-C–H-benzoxylation of 2-arylpyridines using iodobenzene dibenzoates
has been developed, in which the stable and easily accessible hypervalent iodine reagents served as both benzoxylate
source and oxidant. This process showed high regioselectivity and good functional group tolerance, and gave the
mono-benzoxylation products in moderate to excellent yields. It provides a simple and facile synthetically strategy
for the construction of benzoic ester functionalities. Further application of this synthetic methodology is currently
underway in our laboratory.
Acknowledgments
We are grateful to the National Natural Science Foundation of China (NSFC, No. 21302046) and the
Hundred-Talent Program Fund of Hubei University of Technology for financial support.
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Supplementary data
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Supplementary data associated with this article can be found, in the online version, at doi:
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