Efficient synthesis of anthranilic esters via Pd-catalyzed dehydrogenative/decarbonylative coupling of anilides and glyoxylates

Article abstract of DOI:10.1039/c2cc34473d

A novel way of synthesizing anthranilic esters was developed via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates. The Royal Society of Chemistry 2012.

Full text of DOI:10.1039/c2cc34473d

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COMMUNICATION
Efficient synthesis of anthranilic esters via Pd-catalyzed dehydrogenative/
decarbonylative coupling of anilides and glyoxylatesw
Sizhuo Wang, Zhiyong Yang, Jidan Liu, Kai Xie, Anwei Wang, Xiang Chen and Ze Tan*
Received 22nd June 2012, Accepted 7th August 2012
DOI: 10.1039/c2cc34473d
A novel way of synthesizing anthranilic esters was developed via
Pd-catalyzed dehydrogenative/decarbonylative coupling between
anilides and glyoxylates.
ð2Þ
Recently transition metal catalyzed C–H activation of arenes
has been successfully developed as a valuable tool for the
synthesis of a large variety of structurally diverse molecules.1,2
When acetanilide was heated with 2 equiv. of ethyl glyox-
ylate and 4 equiv. of TBHP in the presence of 10 mol% of
Pd(OAc)2 in benzene at 120 1C for 16 h, much to our surprise,
we found that the product isolated in 19% yield was actually
ester A, an anthranilic ethyl ester, not the expected ethyl
phenylglyoxylate (Table 1, entry 1). Somehow a decarbonyla-
tion has taken place during the reaction to produce the ester A.
Since two hydrogen atoms and one molecule of CO were
lost in the process, this reaction can be formally viewed as a
Pd-catalyzed dehydrogenative/decarbonylative coupling between
anilides and ethyl glyoxylate. When the Pd catalyst was switched
to PdCl2, the yield dropped to 12% while the use of Pd(TFA)2
increased the yield substantially to 29% (Table 1, entries 2 and 3).
The use of polar solvents such as DMF or DMSO shuts down
Among the various metal catalysts employed, palladium has
been shown to be the most versatile catalyst for the installation
of functional groups such as halogen,3 hydroxy,4a alkoxy,4b
acetoxy5 and amino6 groups on the arenes through C–C and
C–X bond formations. Besides these functional groups, the
installation of carbonyl groups on the arenes, i.e., the synthesis
of aryl ketones and carboxylates from benzene derivatives via
Pd-catalyzed dehydrogenative coupling has been an area of
intensive research.7–9 For example, Li and others reported
dehydrogenative couplings between 2-aryl pyridines and aryl
aldehydes to produce aryl ketones.7a,b Later on, Kwong et al.7c
successfully extended this protocol to the dehydrogenative
coupling between acetanilides and aryl aldehydes. Even more
impressive is that Li and Deng were able to successfully use
alcohols instead of aldehydes in the couplings, thus increasing
the overall reaction efficiency further.8 While various protocols
based on Pd-catalyzed C–H activation of arenes have been
developed for the synthesis of aryl ketones from benzene
derivatives, only few methods are known to produce aryl
carboxylates.10 Herein we report that anthranilic esters can
be efficiently synthesized via Pd-catalyzed dehydrogenative/
decarbonylative coupling between anilides and glyoxylates.
Inspired by Li and Kwong’s results that, using TBHP as the
oxidant, aldehydes can undergo Pd-catalyzed dehydrogenative
coupling with anilides to produce aryl ketones eqn (1), we
envisioned that phenylglyoxylate can be generated in a similar
fashion if the aldehydes are replaced with glyoxylates eqn (2).
Table 1 Reaction conditions optimization
Entry Catalyst
Temp (1C) Ligand/additive Solvent Yielda (%)
1
2
3
4
5
6
7
8
Pd(OAc)2 120
PdCI2 120
—
—
—
—
—
—
—
Benzene 19
Benzene 12
Benzene 29
Toluene 32
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 130
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
Pd(TFA)2 120
DMF
DMSO
0
0
Toluene 30
Toluene 28
Toluene 41
Toluene 40
Toluene 34
Toluene 30
Toluene 42
Toluene 55
Toluene 66
AgOAc
PPh3
dppe
dppb
1,10-Phen
dppf
dppp
dppp
dppp
9
10
11
12
13
14
15
16
ð1Þ
—
120
Toluene 0
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: +86731 88822400
w Electronic supplementary information (ESI) available. See DOI:
10.1039/c2cc34473d
Reaction conditions: anilide (1 equiv.), Pd-catalyst (10 mol%), TBHP
(4 equiv.), glyoxylate (2 equiv.), solvent (2 mL mmolꢀ1), under N2,
a
b
ligand (10 mol%), 16–24 h. Isolated yields. The reaction was
stopped after 12 h and another 5 mol% of Pd catalyst was added.
c
9924 Chem. Commun., 2012, 48, 9924–9926
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the reaction completely (Table 1, entries 5 and 6). When the
solvent was changed to toluene, the yield was improved
slightly to 32% (Table 1, entry 4). Increasing the reaction
temperature to 130 1C or adding AgOAc as an additive all had
little effect on the reaction yield (Table 1, entries 7 and 8).
Gratifyingly, extensive tests showed that adding phosphine
compounds as additives benefited the reaction. It was discovered
that dppp gave the best yield (55%) whereas other ligands such as
PPh3, dppe, dppb, dppf or N-based ligand 1,10-phen are less
effective (Table 1, entries 9–14). This yield can be further improved
to 66% if the reaction was stopped after 12 h and another
batch of Pd-catalysts was readded (Table 1, entry 15). Since
these phosphine compounds can be oxidized to phosphine
oxides by TBHP in the reaction, the true nature of the ligand is
still unknown at present. However, the benefit of adding a
suitable bidentate phosphine ligand was also observed in Li’s
reaction.8b The test also showed that the use of triphosphine
oxide did not benefit the reaction. Control reaction also
showed that the Pd-catalyst was necessary for the reaction to
proceed (Table 1, entry 16). On the basis of the above results,
we decided to set reaction of 2 equiv. of ethyl glyoxylate with
1 equiv. of anilide and 4 equiv. of TBHP in the presence of
10 mol% of Pd(TFA)2 and 10 mol% of dppp in toluene at
120 1C as our standard protocol.
With the optimized protocol in hand, we next set out to
explore the scope and limitation of the reaction and the results
are summarized in Table 2. We found that the reaction worked
satisfactorily when substituents such as methyl, ethyl and
isopropyl groups were placed on the aromatic ring, affording
the desired anthranilic ester derivatives in yields around 60%
(Table 2, entries 1–3). Substrates with halide substituents were
viable coupling partners too. However, their reaction yields
dropped to below 50% (Table 2, entries 4–7) if a chlorine or
fluorine atom was placed at the 3- or 4-position of the anilide.
On the other hand, alkoxy groups such as methoxy, ethoxy,
nPrO- and nBuO-groups were well tolerated on the anilides and
Table 2 Synthesis of anthranilic esters via Pd-catalyzed dehydrogenative/decarbonylative coupling between anilides and glyoxylates
Entry Anilide
Product
Yielda (%) Entry Anilide
Product
Yielda (%)
1
60
61
62
41
40
8
63
2
3
4
5
9
62
58
54
45
10
11
12
6
7
41
49
13
14
51
47
Reaction conditions: anilide (1 equiv.), Pd-catalyst (10 mol%), TBHP (4 equiv.), solvent (2 mL mmolꢀ1), under N2, dppp (10 mol%), 120 1C,
16–24 h. Isolated yields.
a
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9924–9926 9925

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Currently efforts are underway to elucidate the reaction mecha-
nism 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.
Notes and references
1 (a) G. Dyker, Handbook of C–H Transformations: Applications in
Organic Synthesis, Wiley-VCH, Weinheim, 2005; (b) J. Q. Yu and
Z. J. Shi, C–H Activation, Springer, Berlin, Germany, 2010.
2 For recent reviews, see: (a) C.-L. Sun, B.-J. Li and Z.-J. Shi, Chem.
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J. M. Murphy and J. F. Hartwig, Chem. Rev., 2010, 110, 890;
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(e) O. Daugulis, H.-Q. Do and D. Shabashov, Acc. Chem. Res.,
2009, 42, 1074; (f) X. Chen, K. M. Engle, D.-H. Wang and
J.-Q. Yu, Angew. Chem., Int. Ed., 2009, 48, 5094; (g) F. Kakiuchi and
N. Chatani, Adv. Synth. Catal., 2003, 345, 1077; (h) A. R. Dick and
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X. Chen, Org. Biomol. Chem., 2006, 4, 4041; (j) D. Alberico, M. E. Scott
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A. R. Dick, W. Q. Anani and M. S. Sanford, Org. Lett., 2006, 8, 2523;
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Scheme 1 Possible reaction mechanism.
their couplings with ethyl glyoxylate gave the desired anthranilic
esters in yields ranging from 51–63% (Table 2, entries 8–11). It
should be noted that when a substituent was placed at the
3-position of the anilide, the coupling only took place on the
less hindered side, clearly due to the steric hindrance of the two
existing substituents (Table 2, entries 6, 7 and 13). When the
acetyl group on the amide was replaced with a propionyl group,
the yields of the couplings also dropped to around 45% (Table 2,
entries 12 and 14).
Though the exact mechanism is still not clear at present,
some information has been gathered. When free radical
scavenger BHT was added to the reaction mixture, the reac-
tion was almost completely stopped, suggesting that this
reaction may involve a radical intermediate. This observation
is consistent with what was reported by others.8b On the other
hand, the usually invoked palladation-addition to the carbonyl
group-dehydropalladation mechanism cannot explain the loss
of one molecule of CO during the reaction. We reasoned
that the reaction may be initiated with the Pd(II)-mediated
ortho-palladation of the acetanilide to form intermediate B
(Scheme 1). TBHP was decomposed into alkoxy radicals
which subsequently abstracted the hydrogen off the ethyl
glyoxylate to form radical intermediate C. At elevated temperature,
intermediate C lost one molecule of CO to give intermediate D.
D then reacted with intermediate B to produce the desired anthra-
nilic ethyl ester through either a Pd(IV)11 or Pd(III)12 intermediate.
This proposal is supported by the observation that when ethyl
formate instead of ethyl glyoxylate was reacted with acetanilide
under our standard reaction conditions, the desired anthranilic
ethyl ester could be isolated in 13% yield. Possibly these two
reactions shared the same reaction intermediates such as B
and D. Since not much is known about the reaction, other
mechanisms may be operative here too and a Pd(II) intermediate
cannot be completely ruled out.
8 (a) F. Xiao, Q. Shuai, F. Zhao, O. Basle, G. Deng and C.-J. Li,
´
Org. Lett., 2011, 13, 614; (b) C. A. Correia, L. Yang and C.-J. Li,
Org. Lett., 2011, 13, 4581.
In summary, a novel way of converting anilides into anthranilic
ethyl esters was developed via Pd-catalyzed dehydrogenative/
decarbonylative coupling between anilides and ethyl glyoxylate
using TBHP as the oxidant. The reaction was found to be best run
in toluene using Pd(TFA)2–dppp as the catalyst combination. A
variety of substituted anthranilic ethyl esters were synthesized in
yields of 40–66% and substituents such as alkyl, chloro, fluoro
and alkoxy groups are well tolerated on the anilides. This
method could be complementary to the carbonylation route for
the synthesis of anthranilic acid derivatives from anilides.10a
9 P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898.
10 (a) R. Giri, J. K. Lam and J.-Q. Yu, J. Am. Chem. Soc., 2010, 132, 686;
(b) R. Giri and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14082;
(c) Y. Lu, D. Leow, X. Wang, K. M. Engle and J.-Q. Yu, Chem.
Sci., 2011, 2, 967; (d) W.-Y. Yu, W. N. Sit, K.-M. Lai, Z. Zhou and
A. S. C. Chan, J. Am. Chem. Soc., 2008, 130, 3304.
11 (a) N. R. Deprez and M. S. Sanford, J. Am. Chem. Soc., 2009,
131, 11234; (b) J. M. Racowski, A. R. Dick and M. S. Sanford,
J. Am. Chem. Soc., 2009, 131, 10974.
12 (a) D. C. Powers and T. Ritter, Nat. Chem., 2009, 1, 302;
(b) D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein and
T. Ritter, J. Am. Chem. Soc., 2009, 131, 17050.
c
9926 Chem. Commun., 2012, 48, 9924–9926
This journal is The Royal Society of Chemistry 2012