Palladium-catalyzed C-H acetoxylation of 2-methoxyimino-2-aryl-acetates and acetamides

Article abstract of DOI:10.1039/c1ob05887h

Palladium-catalyzed C-H acetoxylation reactions of 2-methoxyimino-2-aryl- acetates and acetamides have been developed. These transformations feature excellent regioselectivity, wide substrate scope, and moderate to good yields. The product can be easily c

Full text of DOI:10.1039/c1ob05887h

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Palladium-catalyzed C–H acetoxylation of 2-methoxyimino-2-aryl-acetates
and acetamides†
Liang Wang, Xu-Dong Xia, Wei Guo, Jia-Rong Chen and Wen-Jing Xiao*
Received 3rd June 2011, Accepted 28th July 2011
DOI: 10.1039/c1ob05887h
Palladium-catalyzed C–H acetoxylation reactions of 2-
methoxyimino-2-aryl-acetates and acetamides have been de-
veloped. These transformations feature excellent regioselec-
tivity, wide substrate scope, and moderate to good yields. The
product can be easily converted into naturally unprecedented
a-amino acids in excellent yields.
From a chemical perspective, it is important that a directing group
is not only efficient to facilitate direct C–H functionalization, but
also easy to be removed or converted to useful functional groups.
In this regard, Yu and co-workers have developed an oxazoline-
directing conversion of gem-dimethyl groups into cyclopropanes
via Pd-catalyzed C–H activation and a radical cyclization sequence
wherein the oxazoline unit can be readily hydrolyzed to carboxylic
acids.8 In 2007, Daugulis and co-workers successfully employed
carboxylic acids as the directing group in Pd-catalyzed ortho-
arylation of benzoic acids,9,10 which could be removed by decar-
boxylation according to Gooßen’s method.11 Despite advances, to
our knowledge, methoxyimino-acetate and acetamide units have
not yet been utilized in direct C–H functionalization reactions.
Given the significance of such biologically interesting scaffolds, we
reasoned that their functionalization through palladium-catalyzed
C–H acetoxylation process could, in principle, afford structurally
complex methoxyimino-acetate and acetamide derivatives. We
also recognized that the product can be readily converted into
naturally unprecedented a-amino acids.
Methoxyimino-2-aryl acetate and acetamide moieties are an im-
portant class of antifungal pharmacophoric substructures, which
frequently occur in agricultural chemicals and drug candidates.
For instance, Kresoxim-methyl, Dimoxystrobin and Trifloxys-
trobin possess manifold biological activities, such as fungicidal,
insecticidal and herbicidal activities (Fig. 1).1,2 It has been found
that the variation of the substituents on the benzene ring of
these compounds greatly affect their biological activities.3 Not
surprisingly, the development of methods for the preparation of
methoxyimino-acetate and acetamide derivatives with structural
and functional diversity is highly desirable for drug discovery.
The proposed transformation was initially examined using
1.0 equiv. of methoxyimino-acetate 1a and 1.2 equiv. of PhI(OAc)2
in the presence of palladium catalysts (Table 1). To our delight, we
Table 1 Optimization of reaction conditions for C–H acetoxylationa
Fig. 1 Examples of agricultural chemicals bearing methoxyimino-acetate
and acetamide scaffolds.
Over the past decade, transition-metal-catalyzed direct C–H
bond functionalization has been established as one of the most
powerful protocols for the construction of complex molecules.4,5
Basically, nitrogen- or oxygen-containing directing groups are
essential to direct C–H bond functionalization.6 For example,
Sanford and co-workers have disclosed highly regio- and chemos-
elective Pd-catalyzed procedures for the conversion of sp2 and sp3
C–H bonds into esters, ethers, and aryl-halides with the use of N-
heterocycle and O-acetyl oximes as directing groups, respectively.7
Entry
Catalyst
Solvent
T/◦C
Yield (%)b
1c
2d
3
4
5
6
7
8
9
10
11
12
13
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
PdCl2
Pd(PPh3)2Cl2
Pd(CH3CN)2Cl2
Pd(PPh3)4
Pd2(dba)3
Pd(TFA)2
Pd(PhCN)2Cl2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
HOAc
Ac2O
100
100
100
100
100
100
100
100
100
100
80
73
66
83
71
68
65
63
74
73
71
66
80
78
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
HOAc/Ac2O
Key Laboratory of Pesticide & Chemical Biology, Ministry of Education,
College of Chemistry, Central China Normal University, 152 Luoyu Road,
Wuhan, Hubei, 430079, China. E-mail: wxiao@mail.ccnu.edu.cn; Fax: +86
27 67862041; Tel: +86 27 6786 2041
110
120
a Reaction conditions: 1a (0.30 mmol), PhI(OAc)2 (0.36 mmol), Pd(OAc)2
(0.015 mmol, 5 mol%), HOAc (1.0 mL), and Ac2O (1.0 mL). b Isolated
yields. c HOAc (2.0 mL). d Ac2O (2.0 mL).
† Electronic supplementary information (ESI) available: Experimental
procedures and characterization data. CCDC reference number 814555.
For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c1ob05887h
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Table 2 Palladium-catalyzed direct C–H acetoxylation of methoxyimino-
found that 5 mol% of Pd(OAc)2 in HOAc could indeed efficiently
catalyz◦e the reaction and gave the desired product 2a in 73% yield
at 100 C. The structure of 2a was unambiguously confirmed by
the X-ray crystallographic analysis (Fig. 2).12 Encouraged by this
result, we continued to optimize reaction conditions to further
improve the chemical yield. Notably, the yield was drastically
increased to 83% when the reaction was carried out in HOAc–
Ac2O (Table 1, entry 3).13
acetatesa
Entry
1
Substrate
Product
Yield (%)b
83
2
3
4
5
6
7
74
80
80
61
47
66
Fig. 2 X-ray crystal structure of 2a.
Catalyst screening indicated that Pd(OAc)2 displayed the highest
catalytic activity toward the formation of 2a (Table 1, entries 3–
10). The reaction temperature is another critical factor for this
transformation with the best result being attained at 100 ◦C.
Variations of the temperature from this value proved detrimental
for the reaction (Table 1, entries 11–13). Control experiments
showed that no desired product was generated in the absence of
either palladium catalyst or PhI(OAc)2.13
Having established the optimal reaction conditions, we next ex-
amined the substrate scope of the current reaction. As summarized
in Table 2, a series of 2-methoxyimino-2-aryl-acetates are suitable
for this palladium-catalyzed process (Table 2, entries 1–10). A
number of alkyl and alkyoxyl substituents can be incorporated
on the benzene ring at ortho-, meta-, and para-positions without
significant loss in reaction efficiency (Table 2, entries 1–5, R =
Me, MeO, or BnO). It is well known that fluorine can affect
the biological activity of compounds.14 As revealed in entry
6, we have successfully utilized a fluoro-substituted substrate
in this reaction. Furthermore, unsubstituted and disubstituted
methoxyimino-acetates could also be well tolerated to afford the
desired oxidative products in good yields (Table 2, entries 7–10).
Moreover, the aryl framework can be successfully extended to
naphthalene-derived system (Table 2, entry 11). Perhaps more
importantly, the heteroaryl-substituted methoxyimino-acetate 1l
could participate in this C–H acetoxylation reaction albeit with a
low yield (Table 2, entry 12). Interestingly, changing the solvent
to t-BuCO2H resulted in another oxidative coupling product 2s in
57% yield (Table 2, entry 13).
It has been well documented that the ester or amide moiety
of methoxyimino-acetates and acetamides has a significant effect
on their biological activities.2 Accordingly, we have investigated
the structural variation of the ester and amide moieties in the
C–H oxidative acetoxylation reaction. For example, when the
ethoxy was replaced with the methoxy, butoxy, isopropoxy, and
benzyloxy, the corresponding products were obtained in a range
of 72–83% yields (Table 3, entries 1–4). Significantly, we were
pleased to find that the methoxyimino-acetamide 1q and 1r could
8
85
82
56
9
10
11
12
13c
73
17
57
a Reaction conditions: 1 (0.30 mmol), PhI(OAc)2 (0.36 mmol), Pd(OAc)2
(0.015 mmol, 5 mol%), HOAc (1.0 mL), and Ac2O (1.0 mL). b Isolated
yields. c The reaction was carried out in tBuCO2H (2.0 mL).
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Table 3 Palladium-catalyzed direct C–H acetoxylation of methoxyimino-
acetates and acetamidesa
Scheme 2 Synthesis of the a-amino acid derivative 3.
A possible pathway of this palladium-catalyzed C–H acetoxyla-
tion reaction was proposed in Scheme 3. The N of methoxyimino
preferentially coordianted with Pd to form a cyclic Pd complex
I, which might generate the PdIV intermediate II through the
oxidation by PhI(OAc)2.7 The subsequent reductive elimination
would afford the desired product and regenerate the catalyst for
the next catalytic cycle.
Entry
1
Substrate
Product
Yield (%)b
83
2
3
4
5
73
75
72
85
6
76
Scheme 3 Proposed mechanism.
In conclusion, we have developed a palladium-catalyzed direct
C–H acetoxylation reaction of 2-methoxyimino-2-aryl-acetates
and acetamides. The reaction is applicable to a wide range of
substrates with various functional groups and the corresponding
products were obtained in moderate to good yields. Further
application of this methodology to the synthesis of biologically
important compounds is currently ongoing in our group.
a Reaction conditions: 1 (0.30 mmol), PhI(OAc)2 (0.36 mmol), Pd(OAc)2
(0.015 mmol, 5 mol%), HOAc (1.0 mL) and Ac2O (1.0 mL). b Isolated
yields.
also efficiently participate in this oxidative acetoxylation reaction
(Table 3, entries 5–6). To demonstrate the synthetic potential of
the current strategy, the acetoxylation of 1a was carried out on a
gram scale (1.186 g, 5.0 mmol) and product 2a was gained in 73%
yield (Scheme 1).
Acknowledgements
We are grateful to the National Science Foundation of China
(NO. 20872043, 21072069 and 21002036), the National Basic
Research Program of China (2011CB808600), and the Program for
Changjiang Scholars and Inovation Research Team in University
(IRT0953) for support of this research. We thank Mr. Xiao-
Xiao Zhang in this group for reproducing the result of 2a
(Table 1, entry 1).
Scheme 1 A gram-scale experiment for the C–H acetoxylation reaction.
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◦
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3
˚
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6898 | Org. Biomol. Chem., 2011, 9, 6895–6898
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The Royal Society of Chemistry 2011
©