Palladium-catalyzed decarboxylative acylation of O-methyl ketoximes with α-keto acids

Article abstract of DOI:10.1039/c2cc38433g

A mild, practical and efficient palladium-catalyzed decarboxylative ortho-acylation of O-methyl ketoximes with α-keto acids via C-H bond activation is described. In these reactions, a broad range of O-methyl ketoximes and α-keto acids undergoes the decarboxylative cross-coupling reactions with high selectivities and good tolerance. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc38433g

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Palladium-catalyzed decarboxylative acylation
of O-methyl ketoximes with a-keto acids†
Cite this: Chem. Commun., 2013,
49, 925
Minyoung Kim, Jihye Park, Satyasheel Sharma, Aejin Kim, Eonjeong Park,
Jong Hwan Kwak, Young Hoon Jung and In Su Kim*
Received 23rd November 2012,
Accepted 3rd December 2012
DOI: 10.1039/c2cc38433g
www.rsc.org/chemcomm
A mild, practical and efficient palladium-catalyzed decarboxylative ketones.15 Ge et al. described palladium-catalyzed decarboxylative
ortho-acylation of O-methyl ketoximes with a-keto acids via C–H ortho-acylations of acetanilides and phenylpyridines with a-keto
bond activation is described. In these reactions, a broad range of O- acids as acyl sources via C–H bond activation.16 Recently, Guo and
methyl ketoximes and a-keto acids undergoes the decarboxylative Duan et al. reported a decarboxylative acylation of the sp2 C–H bond
cross-coupling reactions with high selectivities and good tolerance. in cyclic enamides with a-keto acids.17
Oximes are common protection groups of the ketone moiety,
Aryl ketones are important structural motifs found in natural and frequently used as directing groups in C–H bond activation
products, medicinally relevant molecules, and functional materials.1 protocols.18 Our continued efforts in transition-metal-catalyzed
In particular, 1,2-diacylbenzenes are known to be crucial synthetic C–H bond activation and oxidative acylation reactions11
precursors to construct a wide range of biologically active prompted us to explore the reaction of O-methyl ketoximes
compounds including phthalazines, phthalimidines, isobenzo- with a-keto acids. In our initial study, 4-fluoroacetophenone
furanes, indanones, isoindoles, and isoindolines.2 These facts have O-methyl oxime (1a) and phenylglyoxylic acid (2a) were chosen
led to increasing interest in developing an efficient method for the as model substrates for optimizing the reaction conditions, and
preparation of 1,2-diacylbenzenes. Traditional metal-catalyzed cross- selected results are summarized in Table 1.
coupling reactions between aryl metal reagents and aryl halides are
To our delight, the combination of Pd(OAc)2 and ammonium
well-established methods for carbon–carbon bond formations.3 persulfate in DCE solvent at 70 1C can catalyze the coupling of 1a
Recently, transition-metal-catalyzed decarboxylative cross-coupling
reactions using aryl carboxylic acids as coupling partners have
Table 1 Selected optimization of the reaction conditionsa
emerged as a promising set of carbon–carbon bond formation
reactions.4 In these reactions, readily available carboxylic acids
enable decarboxylative cross-coupling reactions to proceed with
high selectivities and tolerance of functional groups. Therefore,
decarboxylative cross-coupling reactions provide new alternatives
for Mirozoki–Heck type reactions,5 oxidative arylation,6
redox-neutral biaryls synthesis,7 and allylation.8 Recently, directing-
group-assisted activation of aromatic ortho-C–H bonds, and sub-
sequent acylation reaction by coupling with aldehydes or alcohols
have been reported.9 A variety of directing groups, such as
pyridines,10 amides,11 oximes,12 acetanilides,13 and indole,14 have
been used for C–H bond activation. However, decarboxylative
acylations of aromatic C–H bonds using a-keto acids as acyl
surrogates were relatively unexplored. Goossen et al. first demon-
strated a Pd-catalyzed decarboxylative acylation of aryl bromides with
a-keto carboxylate salts as acyl anion equivalents to afford diaryl
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(TFA)2
Pd(PPh3)2Cl2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
(NH4)2S2O8
K2S2O8
DCE
Toluene
THF
32
12
37
10
45
72
61
27
0
DMF
5
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
6c
7c
8c
9c
10c
11c
12d
41
Trace
0
Ag2O
(NH4)2S2O8
a
School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
E-mail: insukim@skku.edu; Fax: +82 31 292 8800; Tel: +82 31 290 7788
† Electronic supplementary information (ESI) available: Experimental details
and spectroscopic data for all compounds. See DOI: 10.1039/c2cc38433g
Reaction conditions: 1a (0.3 mmol), 2a (0.45 mmol), Pd catalyst
(10 mol%), oxidant (0.45 mmol), solvent (1 mL) for 20 h in pressure
tubes. Isolated yields by flash column chromatography. 3 h. Room
temperature, 20 h.
b
c
d
c
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and 2a to provide an acylated product 3a in 32% yield. Further electron donating group (OMe) at the para-position of acetophenone
screening of solvents showed that diglyme is superior to other O-methyl ketoximes gave a lower yield of decarboxylative coupling
solvents such as toluene, THF, and DMF (Table 1, entries 2–5). product 3e. The acylation reaction of 2-acetonaphthone O-methyl
Interestingly, we found that the coupling reaction between 1a oxime (1f) occurred exclusively at the less sterically hindered
and 2a was completed within 3 h under otherwise reaction position. However, fluoro-substituted ketoxime 1g at the meta-
conditions by TLC monitoring, affording our desired product position furnished the acylated product 3g, albeit providing the
3a in 72% yield (Table 1, entry 6). Thus, we believe that the regioisomers at C6 and C2 with 2 : 1 ratio. These data suggest that
longer reaction times lead to a decrease in chemical yield the steric effect of the substrates strongly interferes with either the
presumably due to the decomposition of the product under formation of the cyclopalladated intermediate or the proximity of
these reaction conditions. As shown in entries 7–11, a range of a-keto acid into the cyclopalladated intermediate. Pleasingly, ortho-
Pd catalysts and oxidants was tested under the identical reaction substituted ketoximes 1h–1k were found to be good substrates for
conditions, but Pd(OAc)2 and (NH4)2S2O8 were found to be best this transformation, affording the corresponding products 3h–3k.
among the other catalysts and oxidants, respectively. However,
this coupling reaction did not proceed at room temperature, range of a-keto acids were screened to couple with tetralone
even for longer reaction time (Table 1, entry 12). O-methyl oxime 1i under optimal reaction conditions (Table 3).
To examine the substrate scope and limitations, a broad
Under the optimized reaction conditions, the reactivity of With either electron-rich or electron-deficient groups, for example
different O-methyl ketoximes was investigated (Table 2). The p-MeO (2b), m-Me (2g), p-CF3 (2c), and m-NO2 (2h) groups, the
coupling of acetophenone O-methyl oximes 1b–1d with electron- decarboxylative coupling reactions underwent smoothly in high
neutral and withdrawing groups at the para-position underwent yields. This transformation also showed good tolerance toward the
smoothly the acylation reaction to afford the corresponding halogen groups. Notably, the chloro and bromo groups offer
products 3b–3d in moderate to high yields. However, a strong versatile synthetic functionality for further elaborations of
the products using other traditional cross-coupling reactions.
Table 2 Scope of O-methyl ketoximesa
Table 3 Scope of a-keto acidsa
a
a
Reaction conditions: 1a–k (0.3 mmol), 2a (0.45 mmol), Pd(OAc)2
Reaction conditions: 1i (0.3 mmol), 2b–m (0.45 mmol), Pd(OAc)2
(10 mol%), (NH4)2S2O8 (0.45 mmol), diglyme (1 mL) in sealed tubes. (10 mol%), (NH4)2S2O8 (0.45 mmol), diglyme (1 mL), 70 1C in sealed
b
c
b
c
Yield isolated by flash column chromatography. Reaction time in tubes. Yield isolated by flash column chromatography. Reaction
d
hours. Regioisomers 3g and 3gg were obtained with 2 : 1 ratio.
time in hours.
c
926 Chem. Commun., 2013, 49, 925--927
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activation. The ongoing studies seek to gain further insight into
the coupling reactions using other directing groups and to
expand the scope to the decarboxylative acylation of sp2 C–H
bonds without directing groups and unactivated sp3 C–H bonds.
This work was supported by National Research Foundation
of Korea (No. 2010-0002465) through the National Research
Foundation of Korea funded by the Ministry of Education,
Science and Technology.
Scheme 1 Expansion of substrate scope from ketoximes to aldoximes.
Notes and references
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Scheme 2 Postulated reaction mechanism.
Meanwhile, a-keto acids 2j and 2k with the naphthyl moiety also
participated in the acylation process with a high reactivity. Finally,
ortho-substituted phenylglyoxylic acid and heterocyclic a-keto acid
were also found to be favored under this catalytic system to afford
the corresponding products 4l and 4m in high yields.
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To evaluate the scope of present catalytic reaction, we expanded
our substrate scope from ketoximes to aldoximes (Scheme 1). To our
pleasure, benzaldehyde O-methyl oximes with electron-neutral and
withdrawing substituents (5a and 5b) were coupled with phenyl-
glyoxylic acid (2a) under the above optimal conditions, albeit in
slightly decreased reactivity. Further detailed optimizations for the
coupling of aldoximes and a-keto acids are in progress.
Although a reaction mechanism is not clear at this stage, it
is believed that this transformation begins with the ortho-
palladation of acetophenone O-methyl oxime (1d) with
Pd(OAc)2 to provide the 5-membered palladacycle I, which
can be subsequently reacted with a-keto acid to afford cyclo-
palladated complex II (Scheme 2). Decarboxylation of cyclopal-
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our desired product 3d. Finally, the regenerated Pd(0) catalyst
can be reoxidized to the active Pd(II) catalyst with (NH)4S2O8.
Although our proposed reaction mechanism is based on Pd(0)
and Pd(II) catalytic cycles, the alternative reaction mechanisms
including Pd(II/III)19 and/or Pd(II/IV)20 catalytic cycles are also
reasonable to consider under strong oxidation conditions.
In summary, we described a Pd-catalyzed decarboxylative
ortho-acylation of O-methyl ketoximes with a-keto acids under
ammonium persulfate as a convenient oxidant via C–H bond
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c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 925--927 927