Decarboxylative acylation of cyclic enamides with α-oxocarboxylic acids by palladium-catalyzed C-H activation at room temperature

Article abstract of DOI:10.1021/ol301801r

An efficient catalytic decarboxylative acylation of unactivated sp ² (alkenyl) C-H bonds has been developed. Various substituted α-oxocarboxylic acids with different electronic properties react under mild conditions to afford a diverse range of β-acyl enamide products in good yields. The reaction is proposed to proceed via a cyclic vinylpalladium intermediate, facilitating the decarboxylative dehydrogenative process with enamide coupling partners.

Full text of DOI:10.1021/ol301801r

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Decarboxylative Acylation of Cyclic
Enamides with r‑Oxocarboxylic Acids by
Palladium-Catalyzed CÀH Activation at
Room Temperature
Hua Wang, Li-Na Guo,* and Xin-Hua Duan*
Department of Chemistry, School of Science and MOE Key Laboratory for
Nonequilibrium Synthesis and Modulation of Condensed Matter, Xi’an Jiaotong
University, Xi’an 710049, China
duanxh@mail.xjtu.edu.cn; guoln81@mail.xjtu.edu.cn
Received July 1, 2012
ABSTRACT
An efficient catalytic decarboxylative acylation of unactivated sp2 (alkenyl) CÀH bonds has been developed. Various substituted R-oxocarboxylic
acids with different electronic properties react under mild conditions to afford a diverse range of β-acyl enamide products in good yields. The
reaction is proposed to proceed via a cyclic vinylpalladium intermediate, facilitating the decarboxylative dehydrogenative process with enamide
coupling partners.
Palladium-catalyzed decarboxylative cross-coupling re-
actions using simple carboxylic acids as coupling partners
have emerged as a new type of CÀC bond formation
reaction.1 In these reactions, using readily available and
stable carboxylic acids instead of organometallic reagents
enabled the decarboxylative cross-coupling reactions to
proceed with good selectivities and tolerance of functional
groups. Goossen,2 Forgione,3 and others4À7 demonstrated
the palladium-catalyzed decarboxylative cross-coupling of
(hetero)aromatic carboxylic,2À4 alkenyl,5 and alkynyl
acids6 and monooxalates7 with organo halides. Myers first
discovered a palladium-catalyzed decarboxylative Heck-
type coupling of olefin with arene carboxylic acids.8 This
concept was further expanded to decarboxylative CÀH
bond activation by Crabtree, Glorius, and others who
disclosed the palladium-catalyzed direct decarboxyla-
tive arylation of unactivated arenes.9 Despite the great
(1) For recent reviews, see: (a) Baudoin, O. Angew. Chem., Int. Ed.
2007, 46, 1373–1375. (b) Goossen, L. J.; Rodrı
Angew. Chem., Int. Ed. 2008, 47, 3100–3120. (c) Satoh, T.; Miura, M.
Synthesis 2010, 3395–3409. (d) Rodrıguez, N.; Goossen, L. J. Chem. Soc.
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Rev. 2011, 40, 5030–5048. (e) Shang, R.; Liu, L. Sci. China Chem. 2011,
54, 1670–1687. (f) Cornella, J.; Larrosa, I. Synthesis 2012, 653–676.
(2) For selected examples, see: (a) Goossen, L. J.; Deng, G.; Levy,
L. M. Science 2006, 313, 662–664. (b) Goossen, L. J.; Rodrı
Melzer, B.; Linder, C.; Deng, G.; Levy, L. M. J. Am. Chem. Soc. 2007,
129, 4824–4833. (c) Goossen, L. J.; Rodrıguez, N.; Linder, C. J. Am.
Chem. Soc. 2008, 130, 15248–15249. (d) Goossen, L. J.; Rodrıguez, N.;
Lange, P. P.; Linder, C. Angew. Chem., Int. Ed. 2010, 49, 1111–1114.
(3) (a) Forgione, P.; Brochu, M.-C.; St-Onge, M.; Thesen, K. H.;
Bailey, M. D.; Bilodeau, F. J. Am. Chem. Soc. 2006, 128, 11350–11351.
(b) Bilodeau, F.; Brochu, M.-C.; Guimond, N.; Thesen, K. H.; Forgione,
P. J. Org. Chem. 2010, 75, 1550–1560.
(4) For some other selected examples, see: (a) Becht, J.-M.; Catala, C.;
Le Drian, C.; Wagner, A. Org. Lett. 2007, 9, 1781–1783. (b) Becht,
J.-M.; Le Drian, C. Org. Lett. 2008, 10, 3161–3164. (c) Miyasaka, M.;
Fukushima, A.; Satoh, T.; Hirano, K.; Miura, M. Chem.;Eur. J. 2009, 15,
3674–3677. (d) Arroyave, F. A.; Reynolds, J. R. Org. Lett. 2010, 12, 1328–
1331. (e) Zhang, F.; Greaney, M. F. Org. Lett. 2010, 12, 4745–4747.
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(5) (a) Wang, Z.; Ding, Q.; He, X.; Wu, J. Org. Biomol. Chem. 2009, 7,
863–865. (b) Yamashita, M.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2010, 12, 592–595.
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H. M.; Lee, S. Org. Lett. 2008, 10, 945–948. (b) Moon, J.; Jang, M.; Lee,
S. J. Org. Chem. 2009, 74, 1403–1406. (c) Kim, H.; Lee, P. H. Adv. Synth.
Catal. 2009, 351, 2827–2832. (d) Park, K.; Bae, G.; Moon, J.; Choe, J.;
Song, K. H.; Lee, S. J. Org. Chem. 2010, 75, 6244–6251.
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r
10.1021/ol301801r
XXXX American Chemical Society

advantages of these reactions, there are still certain limita-
tions including harsh reaction conditions and a narrow
range of carboxylic acids. Thus, further development of
decarboxylative coupling under mild conditions remains a
challenge.
Table 1. Optimization of the Direct Decarboxylative CÀH
Acylation of N-(2H-Chromen-4-yl)acetamide 1a with Phenyl-
glyoxylic Acid 2aa
Ketones are important molecules for organic synthesis,
and numerous methods for the preparation of ketones
have been developed.10 Recently, Goossen first reported
the unsymmetrical diaryl ketone formation using R-
oxocarboxylic acid salts as acyl anion equivalents through
palladium-catalyzed decarboxylative cross-coupling.11
Later, related elegant studies on decarboxylative acylation
of unactivated arenes with R-oxocarboxylic acid via
palladium-catalyzed CÀH activation were also reported
by Ge.12 Among these direct decarboxylative dehydro-
genative cross-coupling examples, unactivated arene and
chelation-assisted sp2 (aryl) CÀH bond activations have been
well-documented.9,12 In sharp contrast, analogous decar-
boxylative dehydrogenative cross-couplings of alkenes via
vinylic CÀH bond activation have been scarcely reported
to the best of our knowledge. Enamides and their deriva-
tives are intrinsically useful intermediates13 and have been
successfully used as a coupling partner in the palladium-
catalyzed CÀH bond activation reaction.14 However,
methods for direct olefin functionalization of enamides
typically rely on the use of organometallic reagents,14a,b
acrylate,14c or arenes,14e and catalytic decarboxylative
dehydrogenative couplings of carboxylic acids with en-
amides have thus far never been investigated. Herein, we
report a palladium-catalyzed decarboxylative acylation of
cyclic enamides with R-oxocarboxylic acid via alkenyl
CÀH bond activation under mild conditions.
yield
(%)b
entry
Pd(II) (mol %)
oxidant (equiv)
K2S2O8 (3.0)
1
Pd(OAc)2 (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)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(OAc)2 (10)
Pd(TFA)2 (10)
Pd(CH3CN)2Cl2 (10)
Pd(PhCN)2Cl2 (10)
PdCl2 (10)
46
10
8
2
(NH4)2S2O8 (3.0)
3
oxone (3.0)
4
Ag2CO3 (3.0)
<5
38
44
55
66
72
80
68
30
20
<5
5
AgOAc (3.0)
6
Ag2O (3.0)
7
K2S2O8 (2.0)/Ag2O (1.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
K2S2O8 (1.0)/Ag2O (2.0)
8
9c
10d
11d
12d
13d
14d
a Reaction conditions: 10 mol % of Pd(II), 1a (0.25 mmol, 1.0 equiv),
2a (0.50 mmol, 2.0 equiv), oxidant (3.0 equiv), solvent (2.5 mL), room
temperature, 20 h. b Yield of isolated product. c 1a (0.25 mmol, 1.0
equiv), 2a (0.375 mmol, 1.5 equiv). d 1a (0.25 mmol, 1.0 equiv), 2a
(0.25 mmol, 1.0 equiv).
decomposed when DME, THF, or diglyme was used as
the solvent.15 After many trials, we discovered that 1a and
2a in the presence of 10 mol % of Pd(OAc)2 and 3.0 equiv
of K2S2O8 in 5% DMSO/DMF (2.5 mL) at room tem-
perature for 20 h led to the desired product 3a in 46% yield
(Table 1, entry 1). Variation of the oxidant showed that
K2S2O8 is superior to other persulfate and silver(I) salts
and over oxone (Table 1, entries 2À6). Further optimiza-
tion demonstrated that the yield could be raised to 55% in
the presence of 2.0 equiv of K2S2O8 and 1.0 equiv of Ag2O
(Table 1, entry 7). When the amount of K2S2O8 was
reduced to 1.0 equiv and the amount of Ag2O was in-
creased to 2.0 equiv, the coupling yield could be further
improved (Table 1, entry 8). To our delight, changing the
ratio of 1a and 2a from 1.0/2.0 to 1.0/1.0 resulted in a
satisfactory yield (Table 1, entry 10). A screening of the
catalysts indicated that Pd(TFA)2 was also effective
(Table 1, entry 11), whereas the others were found to be
inferior (Table 1, entries 12À14).
Our study commenced with the decarboxylative acylation
of N-(2H-chromen-4-yl)acetamide 1a with phenylgly-
oxylic acid 2a to the N-(3-benzoyl-2H-chromen-4-yl)-
acetamide 3a using K2S2O8 as the oxidant and Pd(OAc)2
as the catalyst. Unfortunately, the enamide 1a readily
(9) For selected examples, see: (a) Voutchkova, A.; Coplin, A.;
Leadbeater, N. E.; Crabtree, R. H. Chem. Commun. 2008, 6312–6314.
(b) Wang, C.; Piel, I.; Glorius, F. J. Am. Chem. Soc. 2009, 131, 4194–
4195. (c) Cornella, J.; Lu, P.; Larrosa, I. Org. Lett. 2009, 11, 5506–5509.
(d) Zhou, J.; Hu, P.; Zhang, M.; Huang, S.; Wang, M.; Su, W. Chem.;
Eur. J. 2010, 16, 5876–5881. (e) Xie, K.; Yang, Z.; Zhou, X.; Li, X.;
Wang, S.; Tan, Z.; An, X.; Guo, C.-C. Org. Lett. 2010, 12, 1564–1567.
(f) Zhang, F.; Greaney, M. F. Angew. Chem., Int. Ed. 2010, 49, 2768–
2771. (g) Hu, P.; Zhang, M.; Jie, X.; Su, W. Angew. Chem., Int. Ed. 2012,
51, 227–231.
(10) For reviews, see: (a) Brunet, J.-J.; Chauvin, R. Chem. Soc. Rev.
1995, 24, 89–95. (b) Dieter, R. K. Tetrahedron 1999, 55, 4177–4236.
´
(11) (a) Goossen, L. J.; Rudolphi, F.; Oppel, C.; Rodrıguez, N.
Angew. Chem., Int. Ed. 2008, 47, 3043–3045. (b) Goossen, L. J.;
Zimmermann, B.; Knauber, T. Angew. Chem., Int. Ed. 2008, 47, 7103–
7106. (c) Goossen, L. J.; Zimmermann, B.; Linder, C.; Rodrıguez, N.;
´
Lange, P. P.; Hartung, J. Adv. Synth. Catal. 2009, 351, 2667–2674.
(12) (a) Fang, P.; Li, M.; Ge, H. J. Am. Chem. Soc. 2010, 132, 11898–
11899. (b) Li, M.; Ge, H. Org. Lett. 2010, 12, 3464–3467.
(13) For reviews, see: (a) Carbery, D. R. Org. Biomol. Chem. 2008, 6,
3455–3460. (b) Matsubara, R.; Kobayashi, S. Acc. Chem. Res. 2008, 41,
292–301.
(14) (a) Zhou, H.; Chung, W. J.; Xu, Y. H.; Loh, T. P. Chem.
Commun. 2009, 3472–3474. (b) Zhou, H.; Xu, Y. H.; Chung, W. J.;
Loh, T. P. Angew. Chem., Int. Ed. 2009, 48, 5355–5357. (c) Xu, Y. H.;
Chok, Y. K.; Loh, T. P. Chem. Sci 2011, 2, 1822–1825. (d) Liu, Y.; Li, D.;
Park, C. M. Angew. Chem., Int. Ed. 2011, 50, 7333–7336. (e) Pankajakshan,
S.; Xu, Y. H.; Cheng, J. K.; Low, M. T.; Loh, T. P. Angew. Chem., Int. Ed.
2012, 51, 5701–5705.
Under the optimized reaction conditions, a variety of
substituted phenylglyoxylic acids were found to undergo
efficient decarboxylative acylation with cyclic enamide 1a
at room temperature (Scheme 1). Specifically, phenyl-
glyoxylic acids with p-substituted electron-rich or -
withdrawing groups are all successfully engaged in this reac-
tion (3bÀ3e). It is noteworthy that electronic properties do
(15) For more details, see the Supporting Information.
B
Org. Lett., Vol. XX, No. XX, XXXX

Scheme 1. Scope of R-Oxocarboxylic Acidsa
Scheme 2. Scope of Cyclic Enamidesa
a All reactions were performed with cyclic enamides 1 (0.25 mmol)
and phenylglyoxylic acid 2a (1.0 equiv), under standard conditions
(Table 1, entry 10) at room temperature. Yields are of the isolated
products.
the product 3a was obtained, suggesting that no free
radical intermediate was involved in the reaction.16 Thus,
we proposed the following mechanism for our reaction
(Scheme 3).12,14 The alkenyl CÀH bond activation of
enamide 1 occurs in the presence of the Pd(II) complex
to form a six-membered palladacycle intermediate 5.14c
Anion exchange with R-oxocarboxylic acids gave a Pd
complex 6. Decarboxylation of complex 6 to form the
complex 7 and then reductive elimination of the complex 7
afforded the desired product 3 or 4. Pd(0) is then recycled
back to Pd(II) by the oxidant.
a All reactions were performed with 1a (0.25 mmol) and R-oxocar-
boxylic acids 2 (1.0 equiv), under standard conditions (Table 1, entry 10)
at room temperature. Yields are of the isolated products.
not affect the o-substituted phenylglyoxylic acids since
both electron-donating and -withdrawing groups gave
moderate to good yields (3fÀ3h). Satisfactorily, the β- and
R-naphthyloxoacetic acid also proceeded smoothly to give
the desired products 3i and 3j in 60% and 62% yields,
respectively. Applying furoylformic acid or 2-thienyl-
glyoxylic acid resulted in the desired products in somewhat
lower yields under the above conditions (3k and 3l).
However, aliphatic R-oxocarboxylic acids, such as pyruvic
acid, were inefficient for this decarboxylative CÀH
acylation.
In summary, we have demonstrated that cyclic enamides
participated in efficient intermolecular CÀH bond
Scheme 3. Proposed Catalytic Cycle for Direct Decarboxylative
Acylation Reaction of Cyclic Enamides
To expand the scope of this direct acylation reaction
further, we next investigated the decarboxylative coupling
of phenylglyoxylic acid 2a with other cyclic enamides. As
shown in Scheme 2, all of the 4-chromanone-derived
enamides bearing electron-donating or -withdrawing groups
on the phenyl ring afforded the desired products in moderate
to good yields (4aÀ4d). Acylation of enamide 1e also gave a
modest yield of product 4e. For tetralone-derived enamide,
only a trace amount of product was observed due to the
decomposition of the starting material (4f), whereas protect-
ing the nitrogen atom of the enamide with benzyl group did
not significantly improve the yield.
To gain some understanding of the reaction, 1.0 equiv of
TEMPO, a radical-trapping reagent, was added into the
reaction under the standard conditions. The same yield of
Org. Lett., Vol. XX, No. XX, XXXX
C

acylation reactions. This novel reaction is the first
example of formal vinylic CÀH bond direct functiona-
lization via palladium-catalyzed decarboxylative cross-
coupling reactions. This process provided a useful
method for the preparation of diverse acylated enamides
from readily accessible reactants under mild reaction
conditions.
Acknowledgment. Financial support from National
Natural Science Foundation of China (Nos. 21102110,
21102111) and the Fundamental Research Funds of the
Central Universities are greatly appreciated.
Supporting Information Available. Experimental pro-
cedures and spectroscopic data of new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(16) (a) Anderson, J. M.; Kochi, J. K. J. Am. Chem. Soc. 1970, 92,
1651–1659. (b) Seo, S.; Slater, M.; Greaney, M. F. Org. Lett. 2012, 14,
2650–2653.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX