Synthesis of α -Ketoamides by Copper-Catalyzed Reactions of Phenylacetic Acids with N,N -Dialkylformamides

Article abstract of DOI:10.1080/00397911.2015.1049273

A new synthetic approach for α-ketoamides was achieved by copper-catalyzed coupling reactions between N,N-dialkylformamides and phenylacetic acids. A variety of substrates were well tolerated to give yields of 46-87% (17 examples). A ¹³C-labeli

Full text of DOI:10.1080/00397911.2015.1049273

This article was downloaded by: [New York University]
On: 28 May 2015, At: 08:29
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office: Mortimer House,
37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International Journal
for Rapid Communication of Synthetic Organic
Chemistry
Publication details, including instructions for authors and subscription information:
http://www.tandfonline.com/loi/lsyc20
Synthesis of α-Ketoamides by Copper-Catalyzed
Reactions of Phenylacetic Acids with N,N-
Dialkylformamides
Lanping Zhanga, Junnan Pua, Jiayu Rena, Zhengkai Lia, Haifeng Xianga & Xiangge Zhoua
a Institute of Homogeneous Catalysis, College of Chemistry, Sichuan Universty, Chengdu,
China
Accepted author version posted online: 21 May 2015.
Click for updates
To cite this article: Lanping Zhang, Junnan Pu, Jiayu Ren, Zhengkai Li, Haifeng Xiang & Xiangge Zhou (2015): Synthesis of α-
Ketoamides by Copper-Catalyzed Reactions of Phenylacetic Acids with N,N-Dialkylformamides, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, DOI: 10.1080/00397911.2015.1049273
To link to this article: http://dx.doi.org/10.1080/00397911.2015.1049273
Disclaimer: This is a version of an unedited manuscript that has been accepted for publication. As a service
to authors and researchers we are providing this version of the accepted manuscript (AM). Copyediting,
typesetting, and review of the resulting proof will be undertaken on this manuscript before final publication of
the Version of Record (VoR). During production and pre-press, errors may be discovered which could affect the
content, and all legal disclaimers that apply to the journal relate to this version also.
PLEASE SCROLL DOWN FOR ARTICLE
Taylor & Francis makes every effort to ensure the accuracy of all the information (the “Content”) contained
in the publications on our platform. However, Taylor & Francis, our agents, and our licensors make no
representations or warranties whatsoever as to the accuracy, completeness, or suitability for any purpose of the
Content. Any opinions and views expressed in this publication are the opinions and views of the authors, and
are not the views of or endorsed by Taylor & Francis. The accuracy of the Content should not be relied upon and
should be independently verified with primary sources of information. Taylor and Francis shall not be liable for
any losses, actions, claims, proceedings, demands, costs, expenses, damages, and other liabilities whatsoever
or howsoever caused arising directly or indirectly in connection with, in relation to or arising out of the use of
the Content.
This article may be used for research, teaching, and private study purposes. Any substantial or systematic
reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or distribution in any

form to anyone is expressly forbidden. Terms & Conditions of access and use can be found at http://
www.tandfonline.com/page/terms-and-conditions

Synthesis of α-Ketoamides by Copper-Catalyzed Reactions of Phenylacetic Acids
with N,N-Dialkylformamides
Lanping Zhang1, Junnan Pu1, Jiayu Ren1, Zhengkai Li1, Haifeng Xiang1, Xiangge Zhou1
1Institute of Homogeneous Catalysis, College of Chemistry, Sichuan Universty, Chengdu,
China
E-mail: zhouxiangge@scu.edu.cn
Abstract
A new synthetic approach for α-ketoamides was achieved by copper-catalyzed coupling
reactions between N,N-dialkylformamides and phenylacetic acids. A variety of substrates
were well tolerated to give yields 46-87% (17 examples). 13C-labeling experiment
revealed that the carbonyl group of the products came from the phenylacetic acid.
KEYWORDS: amides, copper, cross-coupling, oxidation
INTRODUCTION
α-Ketoamides constitute key frameworks in many biologically active agents in natural
products such as the immunosuppressive drug rapamycin,[1] and they could serve as
precursors of pharmacologically important structures such as oxazolidinones,[2]
β-lactams,[2,3] and chiral α-hydroxyamides.[4] The importance of the α-ketoamide motif
1

necessitates the development of efficient methods for their preparation. Representative
methods for the construction of α-ketoamides include amidation of α-ketoacids and
α-ketoacylhalides,[5] transition-metal-catalyzed double carbonylative amination of aryl
halides,[6] reaction of isocyanide with aromatic acyl chloride or anhydride followed by
hydrolysis of the resulting α-ketoimidoyl chloride.[7] Besides these methods, Cu-catalyzed
oxidative approaches have also been reported,[8] such as cross-coupling reactions between
formamide and α-oxocarboxylic acids (path 1, Scheme 1),[8a,8b] the reactions between aryl
acetaldehydes or α-carbonyl aldehyde with amines (path 2, Scheme 1),[8c,8d] amidation of
terminal alkynes with anilines (path 3, Scheme 1)[8e] and reactions of aryl methyl ketones
with amines (path 4, Scheme 1).[8f, 8g] More recently, Ahmed and co-workers developed
an elegant procedure for the construction of α-ketoamides involving highly reactive
iminium ions as an intermediate and using DMSO as the oxidant.[8h] However, this
protocol suffered from limited substrate scope in terms of primary amines and was not
suitable for the synthesis of N,N-dialkyl-substitued ketoamides. Nevertheless, most of
these reports are restricted by precursor availability, harsh conditions, multistep processes
or utilization of expensive transition-metal catalysts. Therefore, the development of mild,
convenient and efficient methods toward α-ketoamides is still in challenging, especially
for the synthesis of N,N-disubstituted α-ketoamides.
In continuation of our recent work on copper-catalyzed amidation reactions using DMF
as an amide source,[9] herein is reported copper-catalyzed oxidative reactions of the
2

formation of alpha-ketoacid from alpha-arylacetic acids, and followed by the reaction
with N,N-dialkylformamides to afford α-ketoamides.[10]
RESULTS AND DISCUSSIONS
Initially, we chose phenylacetic acid 1a and DMF 2 as model substrates to optimize the
reaction conditions under oxygen atmosphere. As shown in Table 1, the control
experiment showed that the reaction of phenylacetic acid with DMF failed to give the
expected product 3a in the absence of catalyst (Entry 1, Table 1). Meanwhile, 12% yield
of product 3a was obtained after addition of CuBr and phenanthroline (Entry 2, Table 1).
Subsequent studies revealed that Cu2O was the best copper source to give 42% yield,
while other copper salts, such as CuBr, CuCl, CuI, CuSO4, CuCl2 and Cu(acac)2 resulted
in much lower yields (Entries 2-8, Table 1). Furthermore, other ligands including
bipyridine, TMEDA, DMEDA and L-proline were also investigated, but the results were
unsatisfactory (Entries 9-12, Table 1). Among different additives, pivalic acid exhibited
better results than K2CO3, triethylamine, pyridine, TsOH and HOAc (Entries 13-18, Table
1). Then, various oxidants were examined in the model reaction and the results indicated
that di-tert-butyl peroxide (DTBP) showed to be more beneficial to the reaction than
others including TBHP, K2S2O8 and (NH4)2S2O8 (Entries 19-22, Table 1). The reaction
was further improved by increasing the substrate concentration to afford 3a in 78% yield
(Entry 23, Table 1). Decreasing the temperature resulted in lower yield (Entry 24, Table
1). Therefore, the optimized reaction conditions for the model reaction were Cu2O (10
3

mol%), 1,10-phenanthroline (20 mol%), DTBP (3.0 equiv), PivOH (2 equiv), DMF(1 mL)
at 130 ºC for 24h.
Under the optimized reaction conditions, the scope of substituted phenylacetic acids was
then investigated. As shown in Table 2, the reactions between phenylacetic acids and
DMF proceeded smoothly to give the desired products in moderate to good yields
ranging from 52% to 87%. Some substituents such as methyl, methoxyl and halogens
could be well tolerated during catalysis. Phenylacetic acids with electron-donating groups
seemed to be more beneficial to the reaction than those containing electron-withdrawing
groups. For example, p-tolylacetic acid gave the corresponding product in 87% yield,
while p-nitrophenylacetic acid resulted in only 52% yield (Entries 7 and 8, Table 2).
Meanwhile, steric hindrance seemed to have fewer effects on the results. For example,
phenylacetic acids with methyl group substituted either on para, meta, or ortho position
gave similar yields around 85% (Entries 2, 7 and 10, Table 2). Notably,
1-naphthaleneacetic acid could also be reacted well with DMF to give corresponding
product in 78% yields (Entry 12, Table 2).
Encouraged by these promising results, N, N-diethylformamide could also be applied as
substrate instead of DMF for this reaction. As shown in Table 3, moderate yields were
obtained in these cases indicating the potential of this protocol for the synthesis of
N-substituted α-ketoamides (Table 3).
4

It was reported that DMF could be utilized as a precursor to provide -CONMe2[8a] or
-NMe2[8b] units in the reaction of α-oxocarboxylic acid with DMF. In order to elucidate
the possible reaction pathway of this work, several control experiments were carried out
as shown in Scheme 2. Firstly, benzaldehyde was used instead of phenylacetic acid under
the standard conditions, and desired product 3 couldn’t be obtained, which indicated that
benzaldehyde is not formed as an intermediate (Scheme 2, eqn (1)). Further evidence of a
13C-labeling experiment unambiguously confirmed that the carbonyl group of the product
would come from the phenylacetic acid, rather than DMF (eqn (2), see supporting
information for detail), which seemed this reaction might involve a different pathway
compared with previous work on copper-catalyzed aerobic decarboxylation of
phenylacetic acid by Song et al.[10] Furthermore, after addition of 2 equiv. of TEMPO to
the reaction under standard conditions, the transformation was remarkably suppressed,
suggesting that a free N,N-dimethylamine radical might be involved in the reaction
(Scheme 2, eqn (3)).[8b,8i,11]
On the basis of these and previously reported results,[8b,9] a possible reaction pathway was
proposed as shown in Scheme 3. Initially, phenylacetic acid is oxidized to
2-oxo-2-phenylacetic acid[10b], then, 2-oxo-2-phenylacetic acid forms product with
N,N-dimethylamine radical,[8b] which is formed through decomposition of DMF under the
reaction conditions.[8i,11] This is different from the work of Reddy and coworkers,[12] they
5

showed that amide could be obtained by the decarboxylation of carbamic anhydride
formed from the direct coupling of acid with fomamide.
CONCLUSIONS
In summary, we have discovered a simple method for the synthesis of α-ketoamides via
copper-catalyzed coupling of formamides with phenylacetic acids. 13C-labeling
experiment confirmed that the carbonyl group of the product came from the phenylacetic
acid. This protocol also provides a practical synthetic method for the construction of
N-substituted α-ketoamides.
EXPERIMENTAL SECTION
Typical procedure for the synthesis of N,N-dimethyl-substituted α-ketoamides (3a)
and N,N-diethyl-substituted α-ketoamide (5a) Cu2O (0.05 mmol), PivOH (1.0 mmol),
1,10-phenanthroling (0.1 mmol), DTBP(1.5 mmol), phenylacetic acid (0.5 mmol), and
DMF (1 mL) or DME (1 mL) were added into a Schlenk tube (25 mL) equipped with a
magnetic stirrer bar. The Schlenk tube was then closed and the resulting mixture was
stirred at 130 ºC for 24 h. After cooling down to room temperature, the mixture was
filtered with celite, and the filtrate was washed with water and dried over Na2SO4. The
residue was directly purified by silica gel column chromatography with petroleum
ether/EtOAc (10:1 to 4:1) to give α-ketoamides.
6

SUPPLEMENTAL MATERIAL
Supplemental data for this article can be accessed on the publisher’s website.
ACKNOWLEDGEMENTS
We are grateful to the Natural Science Foundation of China (Nos. 21272161, 21372163,
21472128 and J1103315) and the Ministry of Education of China (No.20120181110050)
for financial support.
REFERENCES
1. (a) Swindells, D. C. N.; White, P. S.; Findlay, J. A. Can. J. Chem. 1978, 56(18), 2491;
(b) Tanaka, H.; Kuroda, A.; Marusawa, H.; Hatanaka, H.; Kino, T.; Goto, T.; Hashimoto,
M.; Taga, T. J. Am. Chem. Soc. 1987, 109(16), 5031; (c) Schreiber, S. L. Science. 1991,
251, 283.
2. Aoyama, H.; Hasegawa, T.; Watabe, M.; Shiraishi, H.; Omote, Y. J. Org. Chem. 1978,
43(3), 419.
3. Hashizume, D.; Kogo, H.; Sekine, A.; Ohashi, Y.; Miyamoto, H.; Toda, F. J. Chem.
Soc., Perkin Trans. 1996, 2, 61.
4. (a) Youn, S. W.; Kim, Y. H.; Hwang, J. W.; Do, Y. Chem. Commun. 2001, 996; (b)
Solodin, I.; Zelcans, Y. G.; Lukevics, E. J. Chem. Soc. Chem.Commun. 1990, 1321.
5. (a) Heaney, F.; Fenlon, J.; McArdleb, P.; Cunningham, D. Org. Biomol. Chem. 2003, 1,
1122; (b) Singh, R. P.; Shreeve, J. M. J. Org.Chem, 2003, 68(15), 6063.
7

6. (a) Ozawa, F.; Soyama, H.; Yanagihara, H.; Aoyama, I.; Takino, H.; Izawa, K.;
Yamamoto, T. Yamamoto, A. J. Am. Chem. Soc. 1985, 107(11), 3235; (b) Liu, J.; Zhang,
R.; Wang, S.; Sun, W.; Xia, C. Org. Lett. 2009, 11(6), 1321; (c) Murphy, E. R.; Martinelli,
J. R.; Zaborenko, N.; Buchwald, S. L.; Jensen, K. F. Angew. Chem. Int. Ed. 2007, 46(10),
1734; (d) Fukuyama, T.; Nishitani, S.; Inouye, T.; Morimoto, K.; Ryu, I. Org. Lett. 2006,
8(7), 1383; (e) Iizuka, M.; Kodo, Y. Chem. Commun. 2006, 1739; (f) Huang, L.; Ozawa,
F.; Yamamoto, A. Organometallics, 1990, 9(9), 2603; (g) Ozawa, F.; Yanagihara, H.;
Yamamoto, A. J. Org. Chem. 1986, 51(3), 415.
7. (a) Chen, J. J.; Deshpande, S. V. Tetrahedron Lett. 2003, 44(49), 8873; (b) Ugi, I.;
Fetzer, U. Chem. Ber. 1961, 94, 1116; (c) Kaim, L. El.; Pinot-Pkigord, E. Tetrahedron,
1998, 54(15), 3799; (d) Mossetti, R.; Pirali, T.;Tron, G. C.; Zhu, J. Org. Lett. 2010, 12(4),
820.
8. (a) Li, D.; Wang, M.; Liu, J.; Zhao, Q.; Wang, L. Chem. Commun. 2013,49, 3640; (b)
Wang, H.; Guo, L.; Duan, X. Org. Biomol. Chem. 2013, 11, 4573; (c) Zhang, C.; Xu, Z.;
Zhang, L.; Jiao, N. Angew. Chem.Int. Ed. 2011, 50(47), 11088; (d) Zhang, C.; Zong, X.;
Zhang, L.; Jiao, N. Org. Lett. 2012, 14(13), 3280; (e) Zhang, C.; Jiao, N. J. Am. Chem.
Soc. 2010, 132(1), 28; (f) Du, F.; Ji, J. Chem. Sci. 2012, 3, 460; (g) Zhang, J.; Wei, Y.; Lin,
S.; Liang, F.; Liu, P. Org. Biomol. Chem. 2012, 10, 9237; (h) Mupparapu, N.; Khan, S.;
Battula, S.; Kushwaha, M.; Gupta, A. P.; Ahmed, Q. N.; Vishwakarma, R. A. Org. Lett.
2014, 16(4), 1152; (i) Zhang, X.; Wang, L. Green Chem. 2012, 14, 2141; (j) Wei, W.;
Shao, Y.; Hu, H.; Zhang, F.; Zhang, C.; Xu, Y.; Wan, X. J. Org. Chem. 2012, 77(17), 7157;
8

(k) Mai, W. P.; Wang, H. H.; Li, Z. C.; Yuan, J. W.; Xiao, Y. M.; Yang, L. R.; Mao, P.; Qu,
L. B. Chem. Commun. 2012, 48, 10117; (l) Grassot, J. M.; Masson, G.; Zhu, J. Angew.
Chem. Int. Ed. 2008, 47(5), 947; (m) Kaïm, L.; Gamez-Montano, R.; Grimaud, L.;
Ibarra-Rivera, T. Chem. Commun. 2008, 1350; (n) Lamani, M.; Prabhu, K. R. Chem. Eur.
J. 2012,18(46), 14638; (o) Wu, X.; Gao, Q. H.; Liu, S.; Wu, A. Org. Lett. 2014, 16(11),
2888; (p) Deshidi, R.; Kumar, M.; Devari, S.; Shah, B. A. Chem. Commun. 2014, 50,
9533.
9. (a) Qu, Y.; Li, Z.; Xiang, H.; Zhou, X. Adv. Synth. Catal. 2013, 355(16), 3141; (b) Hu,
C.; Yan, X.; Zhou, X.; Li, Z. Org. Biomol. Chem. 2013, 11, 8179.
10. (a) Song, Q. L.; Feng, Q.; Yang, K. Org. Lett. 2014, 16(2), 624; (b) Song, Q. L.; Feng,
Q.; Zhou, M. X. Org. Lett. 2013, 15(23), 5990; (c) Feng, Q.; Song, Q. L. Adv. Synth.
Catal. 2014, 356(8), 1697; (d) Feng, Q.; Song, Q. L. J. Org. Chem. 2014, 79(4), 1867.
11. (a) Kumar, G. S.; Maheswari, C. U.; Kumar, R. A.; Kantam, M. L.; Reddy, K. R.
Angew. Chem. Int. Ed. 2011, 50(49), 11748; (b) He, T.; Li, H.; Li, P.; Wang, L. Chem.
Commun. 2011, 47, 8946; (c) Jiang, H.; Lin, A.; Zhu, C.; Cheng, Y. Chem. Commun.
2013, 49, 819.
12. Kumar, P. S.; Kumar, G. S.; Kumar, R. A.; Reddy, N. V.; Reddy, K. R. Eur. J. Org.
Chem. 2013, 1218.
9

Table 1. Selected results from the optimization of the reaction
conditions.a
Entry Catalyst
Oxidant
O2
Ligand Additive Yield b[%]
NR
1
―
―
―
―
―
―
―
―
―
―
―
―
―
2
CuBr
CuCl
CuI
O2
L1
12
3
O2
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L1
L1
10
4
O2
trace
42
5
Cu2O
CuSO4
CuCl2
O2
6
O2
trace
trace
16
7
O2
8
Cu(acac)2 O2
9
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
O2
O2
O2
O2
O2
O2
21
10
11
12
13
14
13
39
trace
NR
23
―
K2CO3
Et3N
10

15
16
17
18
19
20
21
22
23c
24d
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
Cu2O
O2
L1
L1
L1
L1
L1
L1
Py
41
26
24
58
67
40
NR
NR
78
62
O2
TsOH
HOAc
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
PivOH
O2
O2
DTBP
TBHP
(NH4)2S2O8 L1
K2S2O8
DTBP
DTBP
L1
L1
L1
a Reaction conditions: 1a (0.5 mmol), catalyst (10 mol%), oxidant (1.5 mmol), ligand (20
mol%), additive (1.0 mmol), DMF (2 mL), 130 ºC, 24h, O2.
b Isolated yields.
c DMF (1 mL).
d The temperature is 110 ºC.
11

Table 2. Reaction of phenylacetic acids with
DMFa
Entry
1
Readant
Product
Yield b(%)
78
O
N
COOH
O
1a
3a
O
2
3
4
5
6
82
80
67
75
70
N
COOH
O
1b
3b
O
N
COOH
O
OMe
OMe
1c
3c
O
N
COOH
O
F
F
1d
3d
O
COOH
N
Cl
O
Cl
1e
3e
O
N
COOH
O
Br
Br
12

1f
3f
O
7
87
N
COOH
O
1g
1h
3g
3h
O
8
9
52
61
N
COOH
O
O2N
O2N
O
N
COOH
O
Cl
Cl
Cl
Cl
1i
1j
3i
3j
O
N
10
11
83
70
COOH
O
O
N
COOH
O
Cl
Cl
O
1k
1l
3k
3l
N
COOH
12
78
O
a Reaction conditions: phenylacetic acids 0.5 mmol, DMF 1 mL, Cu2O 10 mol%, Phen 20
mol%, PivOH 1.0 mmol, DTBP 1.5mmol, at 130 ºC for 24 h.
b Isolated yields.
13

Table 3. Reaction of phenylacetic acids with
DEFa
Entry
1
Readant
Product
Yield b(%)
57
O
N
COOH
O
1a
1d
5a
5d
O
2
3
46
47
N
COOH
O
F
F
O
N
COOH
O
Cl
Cl
1e
1g
5e
5g
O
4
5
64
61
N
COOH
O
O
N
COOH
O
1j
5j
a Reaction conditions: phenylacetic acids 0.5 mmol, DEF 1 mL, Cu2O 10 mol%, Phen 20
mol%, PivOH 1.0 mmol, DTBP 1.5mmol, at 130 ºC for 24 h.
b Isolated yield.
14

Scheme 1. Methods for the copper-catalyzed preparation of α-ketoamides
15

Scheme 2. Exploring the reaction pathway of formation of α-ketoamides.
16

Scheme 3. Proposed pathway for the synthesis of α-ketoamides.
17