Pd(ii)-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation

Article abstract of DOI:10.1039/c3cc38764j

A palladium-catalyzed decarboxylative acylation of phenylacetamides with α-oxocarboxylic acids via C-H bond activation is described. This protocol provides efficient access to a range of ortho-acyl phenylacetamides, which can be easily converted to 3-isochromanone derivatives. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc38764j

ChemComm
View Article Online
View Journal | View Issue
COMMUNICATION
Pd(II)-catalyzed decarboxylative acylation of
phenylacetamides with a-oxocarboxylic acids
via C–H bond activation†
Cite this: Chem. Commun., 2013,
49, 1654
Received 6th December 2012,
Accepted 7th January 2013
Jihye Park, Minyoung Kim, Satyasheel Sharma, Eonjeong Park, Aejin Kim,
Sang Hwi Lee, Jong Hwan Kwak, Young Hoon Jung and In Su Kim*
DOI: 10.1039/c3cc38764j
www.rsc.org/chemcomm
A palladium-catalyzed decarboxylative acylation of phenylacet- transition-metal-catalyzed oxidative ortho-acylation of benzamides14
amides with a-oxocarboxylic acids via C–H bond activation is with aldehydes, we herein report a palladium-catalyzed ortho-
described. This protocol provides efficient access to a range of acylation of phenylacetamides with a-oxocarboxylic acids via
ortho-acyl phenylacetamides, which can be easily converted to C–H bond activation.
3-isochromanone derivatives.
Our investigation was initiated by exploring the coupling of
N,N-diethyl-2-phenylacetamide (1a) with phenylglyoxylic acid
The development of new carbon–carbon bond-forming reac- (2a), and selected results are summarized in Table 1. To our
tions continues to be an essential goal in organic chemistry.1 delight, the combination of Pd(TFA)2 and (NH4)2S2O8 in
Traditional metal-catalyzed cross-coupling reactions between diglyme solvent promoted the coupling of 1a and 2a to provide
aryl metal reagents and aryl halides are well-established meth- bisacylated compound 3a and monoacylated compound 3aa in
ods for the construction of C–C bonds and synthesis of complex an 1 : 1.8 ratio and in 42% combined yield. After screening of
molecules.2 Recently, transition-metal-catalyzed decarboxyla- solvents under otherwise identical conditions, DCE was found
tive cross-coupling reactions using aryl carboxylic acids as aryl to be the most effective solvent in this coupling reaction,
surrogates have received much attention since such transfor- affording exclusively the bisacylated product 3a in 75% com-
mations provide new opportunities to use readily available bined yield with a >20 : 1 ratio, whereas other solvents such as
carboxylic acids as starting materials for organic synthesis.3 THF, DME and DCM were less effective in the coupling reaction
Transition-metal-catalyzed oxidative acylations of sp2 C–H (Table 1, entries 2–5). Further study showed that Pd(OAc)2
bonds in aromatic compounds with various directing groups,4 displayed the decreased catalytic activity than Pd(TFA)2
e.g., pyridines,5 oximes,6 acetanilides,7 and indole,8 with alde-
Table 1 Selected optimization of reaction conditionsa
hydes or alcohols were reported. However, decarboxylative C–H
bond acylations using a-oxocarboxylic acids as acyl surrogates
are relatively unexplored. Goossen et al. first demonstrated a
palladium-catalyzed decarboxylative cross-coupling reaction of
aryl bromides with a-keto carboxylate salts as acyl anion
equivalents to afford diaryl ketones.9 Ge et al. described an
elegant study of a palladium-catalyzed decarboxylative acyla-
tion of acetanilides and phenylpyridines with a-oxocarboxylic
acids as acyl sources via C–H bond activation.10 Recently, Guo
et al. described a decarboxylative acylation of cyclic enamides
with a-oxocarboxylic acids to obtain b-acyl enamides.11
Entry
Oxidant (equiv.)
Solvent
Yieldb (%)
Ratio (3a : 3aa)c
1
2
3
4
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
(NH4)2S2O8 (3)
K2S2O8 (3)
Diglyme
THF
DME
DCM
DCE
DCE
DCE
42
14
54
64
75
48
32
34
0
1 : 1.8
1 : 20
3 : 1
13 : 1
>20 : 1
8 : 1
5
6d
7e
8
Catalytic C–H bond functionalization of phenylacetamides12
provides direct access to substituted phenylacetamides
and phenylacetic acids, which display a broad range of bio-
logical activities.13 Inspired by our recent studies on a
4 : 1
3 : 1
DCE
DCE
9
Ag2O (3)
10
t-BuO2H (3)
(NH4)2S2O8 (1.5)
DCE
DCE
0
61
11f
1 : 2.4
a
Reaction conditions: 1a (0.3 mmol), 2a (0.9 mmol), Pd(TFA)2 (10 mol%),
oxidant (quantity noted), solvent (1 mL) at 70 1C for 20 h in pressure
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/c3cc38764j
b
c
tubes. Combined isolated yields of 3a and 3aa. Ratio of 3a and 3aa was
1
d
determined by H NMR analysis of a crude reaction mixture. Pd(OAc)2
e
f
(10 mol%). Pd(OAc)2 (10 mol%), TfOH (20 mol%). 2a (1.5 equiv.).
c
1654 Chem. Commun., 2013, 49, 1654--1656
This journal is The Royal Society of Chemistry 2013

View Article Online
Communication
ChemComm
(Table 1, entry 6), and highly electrophilic Pd(OTf)2 generated phenylacetamides 1e–1h were also found to be favored in this
from Pd(OAc)2 and TfOH led to the decomposition of the catalyst system. Notably, the chloro and bromo groups offer
product under our reaction conditions (Table 1, entry 7).15
versatile synthetic functionality for further elaboration of the
Other catalysts including Pd(PPh3)2Cl2, Pd(PCy3)2Cl2, products using other traditional cross-coupling reactions. In
Cp*Rh(CH3CN)3(SbF6)2, and [RuCl2(p-cymene)]2 were also inef- addition, the reaction of meta-substituted phenylacetamides 1i
fective under the present conditions. Screening of the oxidant and 1j preferentially occurred at the more sterically accessible
showed that (NH4)2S2O8 is superior to other oxidants such as position to afford the corresponding product 3i and 3j as a
K2S2O8, Ag2O and t-BuO2H (Table 1, entries 8–10). Logically, it single regioisomer. These data suggest that steric effects of the
was thought that the ratio of 3a and 3aa can be controlled by substrate strongly interfere with either the formation of the
the amount of a-oxocarboxylic acid and oxidant. Indeed, upon cyclopalladated intermediate or the proximity of a-oxocar-
use of 1.5 equiv. of 2a and 1.5 equiv. of (NH4)2S2O8, the boxylic acid to the cyclopalladated intermediate. However, the
monoacylated compound 3aa was obtained as a major com- phenylacetamide with an electron-donating group (OMe) at the
pound in 61% combined yield, albeit resulting in a low level of meta-position failed to deliver the coupling products with
monoselectivity (1 : 2.4), as shown in entry 11.
the current catalyst system.
Due to the rapid bisacylation of symmetrical phenylacet-
To further explore the substrate scope and limitations, a
amides, we focused on the bisacylation of symmetrical phenyl- range of a-oxocarboxylic acids 2b–2j was screened to couple
acetamides 1b–1d using the reaction condition A (Table 1, entry 5) with 2-methoxyphenylacetamide 1e under optimal reaction
and the monoacylation of unsymmetrical phenylacetamides 1e–1j conditions, as shown in Table 3. Electron-rich phenylglyoxylic
using the reaction condition B (Table 1, entry 11), as shown in acids with methoxy or methyl groups at either the para- or meta-
Table 2.
positions proved to be good substrates for this transformation,
Phenylglyoxylic acid (2a) and symmetrical phenylacetamide affording the corresponding products 4b–4d. The para- or meta-
1b with an electron-donating group (OMe) at the para-position substituted phenylglyoxylic acids 2e and 2f with electron-
underwent smooth bisacylation reaction to afford the corre- withdrawing groups (CF3 and NO2) were also found to be
sponding product 3b in 63% yield. However, 4-fluorophenylacet- favoured in the reaction to afford the desired products in good
amide 1c gave the bisacylated compound 3c in 42% yield in yields. The fluoro and chloro moieties on phenylglyoxylic acids
conjunction with the monoacylated compound in 32% yield. were tolerated under these coupling conditions, and afforded
Notably, the phenylacetamide 1d bearing a strong electron- the corresponding products 4g–4i in good yields. Finally,
withdrawing group (CF3) at the para-position afforded 2-(naphthalen-2-yl)-2-oxoacetic acid (2j) also participated in
exclusively a monoacylated compound 3d as a major product the acylation process with a slightly decreased reactivity.
under these reaction conditions. The ortho-substituted
3-Isochromanone and its substituted derivatives are known
to be important synthetic intermediates in organic synthesis.16
Thus we further examined the synthetic utility of the ortho-
acylated phenylacetamides, as shown in Scheme 1. The acylated
Table 2 Scope of phenylacetamidesa
Table 3 Scope of a-oxocarboxylic acidsa
a
Reaction conditions: 1a–j (0.3 mmol), 2a (0.9 mmol for 3a–3d,
a
0.45 mmol for 3e–3j), (NH4)2S2O8 (0.9 mmol for 3a–3d, 0.45 mmol for
Reaction conditions: 1e (0.3 mmol), 2b–j (0.45 mmol), (NH4)2S2O8
b
b
3e–3j), DCE (1 mL) in sealed tubes. Yield isolated by column chromato- (0.45 mmol), DCE (1 mL) in sealed tubes. Yield isolated by column
c
graphy. A monoacylated compound was also obtained in 32% yield.
chromatography.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun., 2013, 49, 1654--1656 1655

View Article Online
ChemComm
Communication
Foundation of Korea funded by the Ministry of Education,
Science and Technology.
Notes and references
1 (a) B. M. Trost, Science, 1991, 254, 1471; (b) P. A. Wender, Chem. Rev.,
1996, 96, 1.
2 (a) J. Magano and J. R. Dunetz, Chem. Rev., 2011, 111, 2177;
(b) A. de Meijere and F. Diederich, Metal-Catalyzed Cross-
Coupling Reactions, Wiley-VCH, Weinheim, 2004.
Scheme 1 Application to the synthesis of 3-isochromanone.
3 For recent reviews, see: (a) J. Cornella and I. Larrosa, Synthesis, 2012,
653; (b) N. Rodriguez and L. J. Goossen, Chem. Soc. Rev., 2011, 40, 5030.
4 For a recent review on catalytic acylation of sp2 C–H bonds, see:
C. Pan, X. Jia and J. Cheng, Synthesis, 2012, 677.
5 (a) X. Jia, S. Zhang, W. Wang, F. Luo and J. Cheng, Org. Lett., 2009,
´
11, 3120; (b) O. Basle, J. Bidange, Q. Shuai and C.-J. Li, Adv. Synth.
´
Catal., 2010, 352, 1145; (c) F. Xiao, Q. Shuai, F. Zhao, O. Basle,
G. Deng and C.-J. Li, Org. Lett., 2011, 13, 1614.
6 (a) C.-W. Chan, Z. Zhou, A. S. C. Chan and W.-Y. Yu, Org. Lett., 2010,
12, 3926; (b) Y. Yang, B. Zhou and Y. Li, Adv. Synth. Catal., 2012,
354, 2916.
7 (a) Y. Wu, B. Li, F. Mao, X. Li and F. Y. Kwong, Org. Lett., 2011,
13, 3258; (b) C.-W. Chan, Z. Zhou and W.-Y. Yu, Adv. Synth. Catal.,
2011, 353, 2999; (c) C. Li, L. Wang, P. Li and W. Zhou, Chem.–Eur. J.,
2011, 17, 10208.
8 B. Zhou, Y. Yang and Y. Li, Chem. Commun., 2012, 48, 5163.
´
9 L. J. Goossen, F. Rudolphi, C. Oppel and N. Rodrıguez, Angew.
Chem., Int. Ed., 2008, 47, 3043.
10 (a) P. Fang, M. Li and H. Ge, J. Am. Chem. Soc., 2010, 132, 11898;
(b) M. Li and H. Ge, Org. Lett., 2010, 12, 3464.
Scheme 2 Proposed reaction mechanism.
11 H. Wang, L.-N. Guo and X.-H. Duan, Org. Lett., 2012, 14, 4358.
12 For a selected example on catalytic functionalization of phenylacet-
amides, see: (a) C. S. Yeung, X. Zhao, N. Borduas and V. M. Dong,
Chem. Sci., 2010, 1, 331; For homodimerization of phenylacetamides,
see: (b) D. G. Pintori and M. F. Greaney, Org. Lett., 2011, 13, 5713.
13 For selected examples of biological activities of phenylacetamide
derivatives, see: (a) J. G. Samaritoni, L. Arndt, T. J. Bruce,
J. E. Dripps, J. Gifford, C. J. Hatton, W. H. Hendrix,
J. R. Schoonover, G. W. Johnson, V. B. Hegde and S. Thornburgh,
J. Agric. Food Chem., 1997, 45, 1920; (b) P. K. Yonan, R. L. Novotney,
C. M. Woo, K. A. Prodan and F. M. Hershenson, J. Med. Chem., 1980,
23, 1102; For selected examples of biological activities of phenyl-
acetic acid derivatives, see: (c) W. R. Hudgins, S. Shack, C. E. Myers
compound 3e, obtained from the reaction of phenylacetamide
1e and phenylglyoxylic acid (2a), was easily converted to
3-isochromanone 6 via reduction of ketone followed by intra-
molecular cyclization under acidic conditions.
Although the reaction mechanism is not clear at this stage, it
is believed that this transformation begins with the ortho-
palladation of phenylacetamide with Pd(TFA)2 to provide the
6-membered palladacycle(II) species I,17 which can be subse-
quently reacted with phenylglyoxylic acid to afford cyclopalla-
dated complex II (Scheme 2).18 Davies and Macgregor
suggested that the acetate anion can facilitate intramolecular
H-transfer via a six-membered transition state.19 In addition,
the trifluoroacetate anion can remarkably improve the electro-
philicity of the Pd center, in comparison with the acetate anion,
thus enhancing the rate of electrophilic metalation.20 Cyclo-
palladation intermediate III, derived from II by the decarboxy-
lation, can undergo reductive elimination to generate our
desirable acylated product, and regenerate the Pd(0) catalyst.
Finally, Pd(0) can be reoxidized to the active Pd(II) catalyst with
(NH)4S2O8. Although our proposed catalytic pathway is based
on Pd(0) and Pd(II) cycles, the alternative mechanistic pathways
involving Pd(II/III)21 and/or Pd(II/IV)22 catalytic cycles are also
reasonable to consider.
´
and D. Samid, Biochem. Pharmacol., 1995, 50, 1273; (d) H. Martınez-
Blanco, A. Reglero and J. M. Luengo, J. Ind. Microbiol., 1994, 13, 144.
14 (a) J. Park, E. Park, A. Kim, Y. Lee, K.-W. Chi, J. H. Kwak, Y. H. Jung
and I. S. Kim, Org. Lett., 2011, 13, 4390; (b) S. Sharma, E. Park, J. Park
and I. S. Kim, Org. Lett., 2012, 14, 906.
15 (a) B. Xiao, Y. Fu, J. Xu, T.-J. Gong, J.-J. Dai, J. Yi and L. Liu, J. Am.
Chem. Soc., 2010, 132, 468; For preparation of Pd(OTf)2, see:
(b) S. Murata and Y. Ido, Bull. Chem. Soc. Jpn., 1994, 67, 1746.
16 (a) K. Kobayashi, T. Mannami, M. Kawakita, J. Tokimatsu and
H. Konishi, Bull. Chem. Soc. Jpn., 1994, 67, 582; (b) R. V. H. Jones,
W. E. Lindsell, G. C. Paddon-Jones, D. D. Palmer, P. N. Preston,
G. M. Rosair and A. J. Whitton, J. Organomet. Chem., 2006, 691, 2378.
17 For a review on palladacycles, see: J. Dupont, C. S. Consorti and
J. Spencer, Chem. Rev., 2005, 105, 2527.
18 From the control experiments using benzaldehyde or methyl ben-
zoylformate instead of phenylglyoxylic acid (2a), we suggest that this
reaction cannot proceed via decarboxylation of a-oxocarboxylic acids
followed by C–H functionalization of the resulting aldehyde or a
Heck-type addition to a CQO bond of a-oxocarboxylic acids fol-
lowed by decarboxylation rather than b-hydride elimination. See the
ESI† for details.
In conclusion, we developed an efficient method for
Pd-catalyzed oxidative ortho-acylation of phenylacetamides with
19 D. L. Davies, S. M. A. Donald and S. A. Macgregor, J. Am. Chem. Soc.,
2005, 127, 13754.
a-oxocarboxylic acids using ammonium persulfate as a con- 20 (a) C. Jia, D. Piao, J. Oyamada, W. Lu, T. Kitamura and Y. Fujiwara,
Science, 2000, 287, 1992; (b) C. Jia, W. Lu, J. Oyamada, T. Kitamura,
K. Matsuda, M. Irie and Y. Fujiwara, J. Am. Chem. Soc., 2000, 122, 7252;
venient oxidant via C–H bond activation. The ongoing studies
seek to gain further insights into the reaction mechanism and
(c) R. Li, L. Jiang and W. Lu, Organometallics, 2006, 25, 5973.
to expand the scope to the acylation of sp2 C–H bonds without 21 D. C. Powers, M. A. L. Geibel, J. E. M. N. Klein and T. Ritter, J. Am.
directing groups and unactivated sp3 C–H bonds.
Chem. Soc., 2009, 131, 17050.
22 (a) C. F. Rosewall, P. A. Sibbald, D. V. Liskin and F. E. Michael, J. Am.
This work was supported by National Research Foundation
Chem. Soc., 2009, 131, 9488; (b) P. A. Sibbald, C. F. Rosewall,
of Korea (No. 2010-0002465) through the National Research
R. D. Swartz and F. E. Michael, J. Am. Chem. Soc., 2009, 131, 15945.
c
1656 Chem. Commun., 2013, 49, 1654--1656
This journal is The Royal Society of Chemistry 2013