Palladium-catalyzed oxime ether directed regioselective C-H alkoxylation of arenes

Article abstract of DOI:10.1080/00397911.2016.1242749

A palladium-catalyzed highly regioselective ortho-C(sp²)-H alkoxylation of oxime ethers with PhI(OAc)₂as the oxidant and alcohols as the alkoxylation reagents has been developed. Mono-alkoxylated and acetoxylated products could be selectively obtained via tuning the reaction conditions. A series of oxime ethers were tolerated, affording the corresponding products in moderate to good yields. Both primary and secondary alcohols survived the reaction conditions. Moreover, the directing group can be easily removed, thereby providing a straightforward access to substituted aryl ketones.

Full text of DOI:10.1080/00397911.2016.1242749

Palladium-Catalyzed Oxime Ether Directed Regioselective C-H Alkoxylation of
Arenes
Liang Pan1, Liang Wang1, Qun Chen1, Mingyang He1
1School of Petrochemical Engineering, Changzhou University, Changzhou, P. R. China
Corresponding author: Liang Wang and Mingyang He, E-mail: lwcczu@126.com;
hemingyangjpu@yahoo.com
Abstract
A palladium-catalyzed high regioselective ortho-C(sp2)-H alkoxylation of oxime ethers
with PhI(OAc)2 as the oxidant and alcohols as the alkoxylation reagents has been
developed. Mono-alkoxylated and acetoxylated products could be selectively obtained via
tuning the reaction conditions. A series of oxime ethers were tolerated, affording the
corresponding products in moderate to good yields. Both primary and secondary alcohols
survived the reaction conditions. Moreover, the directing group can be easily removed,
thereby providing a straightforward access to substituted aryl ketones.
GRAPHICALABSTRACT:
KEYWORDS: C-H activation, oxime ethers, alkoxylation, acetoxylation, palladium
catalysis
1

1. INTRODUCTION
Aryl ethers are very important structural motifs in many natural products,
pharmaceuticals, and materials.[1] Generally, these compounds were synthesized via
classical methods such as Ullmann coupling reactions,[2] Chan-Evans-Lam reactions,[3]
Williamson reactions,[4] and Buchwald-Hartwig couplings.[5] However, some
disadvantages including harsh reaction conditions, the use of expensive reagents, low
atom-economy, as well as the generation of wastes (HX, etc.) may limited their synthetic
applications in some extent.
Over the past decades, catalytic C-H bond functionalization has emerged as a powerful
tool to construct complex chemical frameworks.[6] Particularly, the directing group (DG)
assisted C-H activation is considered as one of the most useful strategies to achieve C-C
and C-X couplings with good regioselectivity, especially for C(sp2)-H bonds.[7] Recently,
the direct alkoxylation of inert C(sp2)-H bond with alcohols using this strategy provides a
feasible route to access aryl ethers. A series of directing groups such as carbonyl,
carbamoyl, acylamino, cyano, azo, triazole, 2-pyridyl, 2-pyridyloxyl, etc. have been
successfully employed for the alkoxylations.[8] Compared with the classical C-O bond
formations mentioned above, no preactivation of arenes is required and wasteful
byproducts are minimized. Despite the remarkable success in this field, there are still two
issues should be pointed out: (1) the alkoxylation of inert C(sp2)-H remains a challenging
2

topic because alkanols are easily oxidized; and (2) some of the reported DGs cannot be
removed, thus resulting in a big drawback for the practical application in organic
synthesis. Thus, development of simple and efficient route for C-H alkoxylation is still
highly desirable.
Recently, our work focused on developing removable DGs-assisted C-O bond formations.
A regioselective palladium-catalyzed ortho-C(sp2)-H acetoxylation of 2-aryloxypyridines
with PhI(OAc)2 as both the oxidant and acetate source was achieved.[9] However, tedious
workup was required for the removal of 2-pyridyloxyl. Our interest led us to explore
substrates with readily removable DGs. In another aspect, oxime ether as a directing
group shows widespread applications in C-H activations.[10] They are readily available or
prepared, and meanwhile, they can be easily removed via simple hydrolysis workup after
C-H activations, thereby providing a facile route to deliver functionalized ketones.
Motivated by previous studies and our interest in this field, we herein report a
palladium-catalyzed regioselective C-H alkoxylation of aryl oxime ethers. Alkoxylation
and acetoxylation products could be selectively obtained via tuning the reaction
conditions (Scheme 1).
2. RESULTS AND DISCUSSION
Our initial studies investigated the methoxylation of the corresponding O-methyl oxime
derivative 1a in methanol (1). Encouragingly, product 3a was obtained in 71% yield in
3

the presence of 10 mol% of Pd(OAc)2 and three equivalents of PhI(OAc)2 at 40 oC.
Meanwhile, 10% yield of di-methoxylated product 3a' was also isolated. No acetoxylated
product 3a was observed under this condition (Table 1, entry 1). Other palladium salts
including PdCl2, Pd(PPh3)4, PdCl2(CH3CN)2 and Pd(TFA)2 gave inferior results (Table 1,
entries 2~5). A series of oxidants were then tried. Much lower yields were obtained when
oxone and K2S2O8 were used, while the BQ (benzoquinone), Cu(OAc)2 and oxygen were
completely ineffective for this reaction (Table 1, entries 6, 9 and 10). No improvement
was observed when increasing the amount of PhI(OAc)2 to five equivalents, while 52%
yield of 3a was obtained when using two equivalents of the oxidant. The mixed solvents
such as MeOH/DCE, MeOH/CH3CN and MeOH/dioxane were also tested, and the results
clearly showed that addition of other solvents reduced the yields obviously (Table 1,
entries 13~15), which was might attributed to the fact that a low concentration of alcohol
was unfavorable for this reaction. Moreover, the addition of AcOH, TFA and TsOH still
did not improve the yields (Table 1, entries 16~18). The temperature significantly affect
this reaction, especially for the Pd(OAc)2/PhI(OAc)2 system, since the acetoxylated
product could be easily generated.[8b,8g,9] As expected, reaction at 60 oC afforded only
51% yield of the desired product 3a, while a satisfactory yield (74%) of acetoxylated
product 4a was obtained when performing the reaction at a higher temperature (80 oC).
Finally, decreasing the catalyst amount to 5 mol% also provided a low yield of 3a.
4

Having established the optimized reaction conditions, the substrates scope was next
examined. The results are summarized in Table 2. For the methoxylation, a series of
O-methyl oxime ethers with substituents such as methyl, methoxyl, halogens (Cl, Br)
survived the reaction conditions, affording the corresponding products in moderate to
good yields. However, substrate with strong electron-withdrawing group, for example,
the nitro group, failed to provide the desired product. For the meta-substituted substrates,
the reaction selectively took place on the side with smaller steric hindrance (3g and 3h).
Interestingly, no reaction occurred for the ortho-substituted substrates with the present
reaction conditions; while moderate yields were obtained (3i: 64%; 3j: 51%) by
switching the oxidant to oxone. This phenomenon was also observed for
(E)-benzaldehyde O-methyl oxime (3k). Moreover, a high yield (85%) of product 3l was
obtained by employing oxime ether 1l which was derived from
3,4-dihydronaphthalen-1(2H)-one. Other alcohols, such as ethanol, isopropanol,
n-butanol and tert-butyl alcohol were also checked as the alkoxylation reagents. The
desired ortho-alkoxylation products 3m~3o were obtained in acceptable to moderate
yields, while tert-butyl alcohol showed no reactivity towards this reaction. It should be
pointed out that mono-alkoxylated products were identified as the major products in all
cases, together with trace amounts of di-alkoxylated ones.
As mentioned above, acetoxylation reaction was observed as the major reaction at an
elevated temperature. Therefore, a selected number of oxime ethers was tested. Pleasingly,
5

all of them tolerated the reaction conditions to afford the corresponding acetoxylated
products in good yields (Table 3).
The synthetic utilities of present protocol was also demonstrated in Scheme 2. Using
compounds 3a and 4a as examples (0.5 mmol scale), both the oxime ether and the acetyl
group can be removed by the treatment with HCl in Et2O at room temperature, thereby
providing a feasible route to access ortho-methoxy or ortho-hydroxy aryl ketones (5,
92% and 6, 84%, respectively).
On the basis of the literatures[8b,11] and our previous experimental results,[9] a plausible
mechanism was outlined in Scheme 3. First, the reaction may involve the formation of a
C-Pd bond to generate the five-membered palladacycle intermediate A. Then, the
oxidation of intermediate A in the presence of PhI(OAc)2 and an alcohol will form Pd(IV)
intermediate B . Finally, the formation of the C-O bond affords the alkoxylated product
and regenerates the catalyst via reductive elimination.
3. CONCLUSION
In summary, a palladium-catalyzed high regioselective ortho-C(sp2)-H alkoxylation of
oxime ethers with PhI(OAc)2 as the oxidant and alcohols as the alkoxylation reagents has
been developed. Mono-alkoxylated products were indentified as the major products at 40
oC, while a higher temperature (80 oC) favored the C-H acetoxylation reaction. A series
6

of functional groups survived the reaction conditions, affording the corresponding
products in moderate to good yields. This protocol is also available for both primary and
secondary alcohols. Importantly, the directing group can be easily removed, thereby
providing a straightforward access to substituted aryl ketones.
4. EXPERIMENTAL
4.1. General Remarks
Chemicals were used as received without special purification unless stated otherwise.
Melting points (m.p.) are determined with an Optimelt MPA 100 apparatus and are not
corrected. 1H and 13C NMR spectra were recorded on a Bruker Advance 300 analyzer in
Chloroform-d (CDCl3) using TMS as an internal standard. The coupling constants J are
given in Hz. High-resolution mass spectrometry (HRMS) was performed on a TOF MS
instrument with an ESI source.
General procedure for palladium-catalyzed alkoxylation and acetoxylation: a sealed
tube equipped with a magnetic stirrer bar was charged with oxime ether 1a (0.2 mmol),
Pd(OAc)2 (0.02 mmol, 10 mol%), and PhI(OAc)2 (0.6 mmol, 3.0 equiv) in an alcohol 2 (1
mL). The reaction mixture was stirred at 40 oC for 24 h (for acetoxylation, reaction was
performed at 80 oC). After reaction, the mixture was allowed to cool to room temperature.
The solvent was then removed under vacuum, and the residue was purified by silica gel
7

chromatography using a mixture of petroleum ether/EtOAc to afford the desired product
3 or 4.
(E)-1-(2-methoxyphenyl)ethan-1-one O-methyl oxime (3a). Yellow oil; 1H NMR (300
MHz, CDCl3) δ 7.33-7.29 (m, 2H), 6.97-6.88 (m, 2H), 3.98 (s, 3H), 3.83 (s, 3H), 2.18 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 157.4, 156.6, 130.1, 129.5, 126.9, 120.6, 110.9, 61.6,
55.4, 15.9; HRMS (ESI): Calcd for C10H13NNaO2 (M + Na)+ 202.0838, found 202.0849.
(E)-2-(1-(methoxyimino)ethyl)-5-methylphenyl acetate (4b). Yellow oil; 1H NMR (300
MHz, CDCl3) δ 7.31 (d, J = 7.9 Hz, 1H), 7.08-7.04 (m, 1H), 6.90 (d, J = 0.7 Hz, 1H),
3.95 (s, 3H), 2.35 (s, 3H), 2.27 (s, 3H), 2.14 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.4,
153.3, 147.6, 140.1, 129.1, 127.2, 126.8, 123.6, 61.8, 21.0 (2C), 14.9; HRMS (ESI):
Calcd for C12H15NNaO3 (M + Na)+ 244.0944, found 244.0950.
General procedure for the synthesis of 3i~3k: Oxone (0.6 mmol, 3.0 equiv) and
Pd(OAc)2 (0.02 mmol, 10 mol%) were combined in MeOH (1 mL) in a tube. Substrate 1a
(0.2 mmol, 1.0 equiv) was then added to the mixture. The tube was sealed, and the
reaction mixture was stirred at room temperature for 12 h. Then the temperature was
slowly ramped to 80 oC for another 12 h. The reaction mixture was diluted with ethyl
acetate and extracted with water (2 x 5 mL), NaHCO3 (2 x 5 mL), and brine (2 x 5 mL).
8

The organic layer was dried over MgSO4, filtered and concentrated. The resulting oil was
purified by chromatography on silica gel to afford the desired products.
ACKNOWLEDGMENTS
This project was financially supported by the National Natural Science Foundation of
China (NO. 21302014).
SUPPORTING INFORMATION
Full experimental detail, characterization data, 1H and 13C NMR spectra. This material
can be found via the “Supplementary Content” section of this article’s webpage.
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Table 1. Optimization of reaction conditions.[a]
Catalyst
(mol%)
Oxidant
(equiv)
Entry
Solvent
Additive Yield(%)[b]
(equiv)
3a 3a'
4a
0
Pd(OAc)2 (10) PhI(OAc)2 MeOH
(3)
none
1
2
3
4
5
71 10
PdCl2 (10)
PhI(OAc)2 MeOH
(3)
none
33 <5
0
0
0
0
Pd(PPh3)4 (10) PhI(OAc)2 MeOH
none
37 <5
(3)
PdCl2(CH3CN)2 PhI(OAc)2 MeOH
none
43 <5
(3)
Pd(TFA)2 (10) PhI(OAc)2 MeOH
(3)
none
47 <5
Pd(OAc)2 (10) BQ (3)
MeOH
none
6
7
8
0
0
0
0
0
Pd(OAc)2 (10) Oxone (3) MeOH
none
none
35 <5
19 0
Pd(OAc)2 (10) K2S2O8
(3)
MeOH
Pd(OAc)2 (10) Cu(OAc)2 MeOH
(3)
none
9
0
0
0
12

Pd(OAc)2 (10) O2 (1 atm) MeOH
none
none
10
11
0
0
0
0
Pd(OAc)2 (10) PhI(OAc)2 MeOH
68 12
52 <5
45 <5
41 <5
36 <5
63 <5
21 <5
15 <5
42 0
(5)
Pd(OAc)2 (10) PhI(OAc)2 MeOH
(2)
none
12
0
0
0
0
0
0
0
0
6
Pd(OAc)2 (10) PhI(OAc)2 MeOH/DCE
none
13
(3)
Pd(OAc)2 (10) PhI(OAc)2 MeOH/MeCN none
(3) (1:1)
Pd(OAc)2 (10) PhI(OAc)2 MeOH/dioxane none
(3) (1:1)
(1:1)
14
15
Pd(OAc)2 (10) PhI(OAc)2 MeOH
AcOH
(5)
16
(3)
Pd(OAc)2 (10) PhI(OAc)2 MeOH
TFA (5)
17
(3)
Pd(OAc)2 (10) PhI(OAc)2 MeOH
(3)
TsOH
(5)
18
Pd(OAc)2 (10) PhI(OAc)2
MeOH
none
19[c]
20[d]
21[e]
(3)
Pd(OAc)2 (10) PhI(OAc)2
MeOH
none
none
51 10
(3)
Pd(OAc)2 (10) PhI(OAc)2
MeOH
5
trace 74
(3)
13

Pd(OAc)2 (5)
PhI(OAc)2
(3)
none
22
MeOH
48 <5
0
[a] Reaction conditions: 1a (0.2 mmol), catalyst (10 mol%), solvent (1 mL), oxidant (3.0
equiv) at 40 oC, air, 24 h. [b] Isolated yield. [c] room temperature. [d] Reaction at 60 oC. e
Reaction at 80 oC.
14

Table 2. Pd-catalyzed ortho-alkoxylation of oxime ethers.[a]
[a] Reaction conditions: 1a (0.2 mmol) and alcohol (1 mL), Pd(OAc)2 (10 mol%),
PhI(OAc)2 (3.0 equiv), 40 oC, air, 24 h, isolated yields. [b] Oxone (3 equiv) as the oxidant,
rt for 12 h; then 80 oC for 12 h. [c] Ratio of Z/E isomers determined by 1H NMR.
15

Table 3. Pd-catalyzed ortho-acetoxylation of selected oxime ethers.[a]
[a] Reaction conditions: 1a (0.2 mmol) and CH3OH (1 mL), Pd(OAc)2 (10 mol%),
PhI(OAc)2 (3.0 equiv), 80 oC, air, 24 h, isolated yields.
16

Scheme 1. Palladium-catalyzed oxime ether directed C-O bond formation
17

Scheme 2. Synthetic utilities of present protocol
18

Scheme 3. Plausible mechanism
19