Pd-catalyzed decarboxylative ortho-acylation of O-methyl oximes with phenylglyoxylic acids

Article abstract of DOI:10.1039/c2cc38861h

Aryl ketones were synthesized via Pd-catalyzed decarboxylative coupling between O-methyl oximes and phenylglyoxylic acids using (NH₄) ₂S₂O₈ as the oxidant. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c2cc38861h

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Pd-catalyzed decarboxylative ortho-acylation of
O-methyl oximes with phenylglyoxylic acids†
Cite this: Chem. Commun., 2013,
49, 1560
Zhiyong Yang, Xiang Chen, Jidan Liu, Qingwen Gui, Kai Xie, Miaomiao Li and
Ze Tan*
Received 17th October 2012,
Accepted 3rd January 2013
DOI: 10.1039/c2cc38861h
www.rsc.org/chemcomm
Aryl ketones were synthesized via Pd-catalyzed decarboxylative Guo et al. developed a similar Pd-catalyzed decarboxylative coupling
coupling between O-methyl oximes and phenylglyoxylic acids between enamides and a-oxocarboxylic acids to produce
using (NH4)2S2O8 as the oxidant.
b-amino substituted a,b-unsaturated ketones.11f Herein we report that
this decarboxylative acylation with a-oxocarboxylic acids can be
The development of Pd-catalyzed decarboxylative couplings1 has been extended to O-methyl oximes (eqn (2)).18–20
an area of intensive research lately since these couplings do not require
the use of usually expensive organometallic reagents.2–16 Instead they
utilize readily available carboxylic acids which, in principle, only
produce CO2, an innocuous compound, as the side-product after
undergoing decarboxylation. Since the pioneering studies by Myers
et al. and Goossen et al.,2,3 a number of different Pd-catalyzed
decarboxylative couplings have been developed to access styrenes,3,4
biaryls,2,5–10 ketones,11 esters,12 nitriles,13 diarylmethanes,14 and
(1)
(2)
Initial experiments started with the reaction of phenylglyoxylic acid
with O-methyl benzaldoxime using Ge’s protocol. When O-methyl
benzaldoxime was treated with 2 equiv. of phenylglyoxylic acid in the
presence of 10 mol% of Pd(TFA)2 and 2 equiv. of (NH4)2S2O8 in
diglyme at room temperature for 12 h, much to our delight, the desired
ketone product was produced in 10% yield and the major side-product
was benzaldehdye resulting from the hydrolysis of the starting oxime.
phenanthrenes.15 Among these couplings, those relying on the direct
arylation of arene approach5b,7,11b,c,f,15,16 are particularly noteworthy
since these transformations are C–H activation based.17 For example,
Crabtree et al. were the first to merge oxidative decarboxylative
couplings with C–H activation in their Pd-catalyzed decarboxylative
biaryl synthesis.5b They also showed that an intramolecular version of
this reaction was able to give dibenzofuran in moderate yield. This
transformation was further developed by Glorius et al. into a high
yielding method for the synthesis of dibenzofurans via Pd-catalyzed
decarboxylative cyclization of ortho-phenoxy benzoic acids.16 Larrosa
et al. and Su et al. reported the intermolecular decarboxylative
couplings between indole or thiophene derivatives and aryl carboxylic
acids.7 Zhang and Greaney and our group discovered that benzo-
thiazoles and oxazoles can also undergo intermolecular decarboxylative
couplings with aryl carboxylic acids.8 By using polyfluorobenzene as the
coupling partner, this decarboxylative coupling can be adapted for the
synthesis of polyfluorobiaryls.8a,9 Similarly, the synthesis of ketone via
Pd-catalyzed decarboxylative coupling can also be C–H activation
based. For example, Ge et al. recently reported the direct ortho-acylation
of acetanilides (eqn (1)) and 2-aryl pyridines via Pd-catalyzed decarbox-
ylative coupling with a-oxocarboxylic acids.11b,c Following this report,
Table 1 Reaction condition optimizationa
Entry
PdX2 (mol%)
Oxidant (equiv.)
Solvent
Yieldb (%)
1
2
3
4
5
6
Pd(TFA)2 (10)
Pd(OAc)2 (10)
PdCl2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
—
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
Ag2CO3 (3)
Oxone (2)
(NH4)2S2O8 (2)
K2S2O8 (2)
Diglyme
Diglyme
Diglyme
DMSO
1,4-Dioxane
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
Diglyme
53
60
Trace
0
0
0
7
10
57
31
0
67
71
8c
9
10
11d
12e
(NH4)2S2O8 (2)
(NH4)2S2O8 (2)
(NH4)2S2O8 (3)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry
and Chemical Engineering, Hunan University, Changsha 410082, P. R. China.
E-mail: ztanze@gmail.com; Tel: +86 731 88822400
a
Conditions: 1a (0.5 mmol), 2a (1.0 mmol), PdX2 (0.05 mmol), oxidant
b
(1.0 mmol), 3 mL of solvent, rt, 12 h unless otherwise noted. Yields
c
† Electronic supplementary information (ESI) available: Detailed experimental
procedures and characterization of all products. See DOI: 10.1039/c2cc38861h
are based on 1a, determined by GLC. 12 h in the presence of 1 atm of
d
e
O2. 60 1C, 12 h. 5 mL of solvent, 35 1C, 12 h.
c
1560 Chem. Commun., 2013, 49, 1560--1562
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Despite numerous attempts, the yield could not be improved. However, Table 2. We found that the reaction worked well when an alkyl or
attempt to couple phenylglyoxylic acid with ortho-methyl-substituted alkoxyl substituent was placed at the ortho-position of the benzal-
O-methyl benzaldoxime (1a) resulted in a much better yield (53%, doximes, affording the desired substituted ketones in yields ranging
Table 1, entry 1). This may have to do with the stability of the from 65–79% while a chloro-substituent caused a significant drop in
compound under the reaction conditions. This yield can be increased yield when it was placed at the ortho position of the benzaldoximes
to 60% if the Pd(TFA)2 catalyst was replaced by Pd(OAc)2 (Table 1, (Table 2, entries 5 and 6). In addition, only a trace amount of the
entry 2) while the use of PdCl2 only gave trace amounts of the desired desired product was obtained when the chloro atom was replaced with
product (Table 1, entry 3). When the solvent was switched to DMSO a fluoro atom (not shown in Table 2). Since the best yield of 79% was
or 1,4-dioxane, no reaction took place (Table 1, entries 4 and 5). achieved with an alkoxy group (Table 2, entry 8), this suggested that
Substituting the oxidant (NH4)2S2O8 with Oxone or Ag2CO3 led to a electron-donating groups may actually benefit the reaction. The reac-
disastrous failure (Table 1, entries 6 and 7) while the use of K2S2O8 as tion also worked well when the O-methyl group was replaced with an
the oxidant only gave a 31% yield. Control reaction also indicated that O-benzyl group (Table 2, entries 2, 4 and 6). However, if the oxime was
the Pd-catalyst was necessary for the reaction to proceed (Table 1, derived from a ketone, the yield dropped to 35% (Table 2, entry 10).
entry 10). Finally we discovered that better yields could be obtained by
As for the phenylglyoxylic acids, substituents such as the fluoro-,
raising the reaction temperature and varying the amount of solvent chloro-, phenyl-, and methyl group on the aromatic ring are well
and oxidant used, and the best yield of 71% was obtained at 35 1C tolerated, affording the desired ketones in 63–85% yields (Table 3).
(entries 11 and 12). Based on these results, we decided to set reacting Naphthyl glyoxylic acids also worked satisfactorily (Table 3, entries 5
the O-methyl benzaldoxime with 3 equiv. of (NH4)2S2O8 in the presence and 6). It is interesting to see that reactions employing furanyl and
of 10 mol% Pd(OAc)2 in diglyme at 35 1C as our standard conditions. thiophenyl glyoxylic acids all proceeded without any problem and the
With the optimized protocol in hand, we next set out to explore the heterocycles remained intact under the reaction conditions (Table 3,
scope and limitation of the reaction and the results are summarized in entries 9 and 10). Unfortunately, couplings with alkylglyoxylic acids
did not give the desired products in synthetically useful yields.
Table 2 Pd-catalyzed ortho-acylation of substituted O-alkyl oximes with phenyl-
glyoxylic acida
Table 3 Pd-catalyzed ortho-acylation of substituted O-methyl oximes with
various phenylglyoxylic acidsa
Entrya
1
Acid
Product
Yieldb (%)
71
Entrya
1
Acid
Product
Yieldb (%)
63
65
75
2
3
2a
2a
65
2
3
69
72
70
1b
73
4
2a
4
5
6
7
8
1a
1a
1a
1a
1a
49
43
5
6
7
8
2a
2a
2a
2a
67
85
68
70
79
73
35
9
2a
2a
64
60
9
1a
1a
10
a
10
a
Conditions: 1a–b (0.5 mmol), 2a–j (1.0 mmol), Pd(OAc)2 (0.05 mmol),
(NH4)2S2O8 (1.5 mmol), 5 mL of diglyme, 35 1C, 9–36 h. Isolated yields
Conditions: 1a–k (0.5 mmol), 2a–b (1.0 mmol), Pd(OAc)2 (0.05 mmol),
(NH4)2S2O8 (1.5 mmol), 5 mL of diglyme, 35 1C, 12 h. Isolated yields
b
b
based on 1.
based on 1.
c
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Scheme 1 Mechanism probing.
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Scheme 2 Possible reaction mechanism.
Some control reactions were performed to probe the possible reac-
tion intermediate (Scheme 1). According to the reported procedure,20d
the 5-membered palladacycle I-a was prepared by reacting O-methyl
benzaldoxime 1a with Pd(OAc)2 in TFA. Then the isolated palladacycle
I-a was treated with phenylglyoxylic acid in diglyme under N2. No
reaction took place with or without the addition of K2CO3 (eqn (3) and
(4)) and the desired product 3a was isolated in 63% yield when
(NH4)2S2O8 was added (eqn (5)). These results suggested that the
critical step of the reaction may actually involve a Pd(III) or Pd(IV)
intermediate,21 not a Pd(II) intermediate. On the basis of these results,
one plausible mechanism is proposed and shown in Scheme 2. The
reaction may be initiated with Pd(II)-mediated C–H activation of the
ortho-position of the O-methyl oxime to form intermediate I. This
intermediate will undergo anion exchange with the glyoxylate ion to
form intermediate II which will lose one molecule of CO2 in the
presence of (NH4)2S2O8 to form the acyl-Pd(III or IV) intermediate III.
The desired ketone product is produced after reductive elimina-
tion and the Pd(II) catalyst is regenerated, thus completing the
catalytic cycle.
In summary, we demonstrated that aryl ketones could be synthe-
sized via Pd-catalyzed acylation of O-methyl oximes with phenyl-
glyoxylic acids. Similar to Ge’s reaction, this reaction proceeded
satisfactorily under mild conditions using cheap (NH4)2S2O8 as the
oxidant. While the reaction of ortho-unsubstituted oximes failed, the
ortho-substituted oximes reacted well to afford a wide variety of
ketones in 35–85% yields. Currently efforts are underway to expand
the reaction scope and the results will be reported in due course.
This work is supported by grants from the National Science
Foundation of China (No. 21072051), NCET program (NCET-
09-0334) and the Fundamental Research Funds for the Central
Universities, Hunan University.
´
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19 After the completion of the reviewing process of this manuscript, an
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oximes with phenylglyoxylic acids was reported: M. Kim, J. Park,
S. Sharma, A. Kim, E. Park, J. H. Kwak, Y. H. Jung and I. S. Kim,
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Notes and references
1 For some reviews on decarboxylative couplings, see (a) L. J. Goossen,
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c
1562 Chem. Commun., 2013, 49, 1560--1562
This journal is The Royal Society of Chemistry 2013