Copper-catalyzed oxidative amidation between aldehydes and arylamines under mild conditions

Article abstract of DOI:10.1016/j.tetlet.2014.12.113

A facile strategy to prepare amide bonds has been developed. A series of amide compounds, including heterocyclic amide compounds, were obtained with moderate to good yields ranging from 31-88% by using copper iodide (CuI) to catalyze the oxidative amidation between aldehydes and amines under solvent-free conditions at room temperature in air.

Full text of DOI:10.1016/j.tetlet.2014.12.113

Accepted Manuscript
Copper-Catalyzed Oxidative Amidation between Aldehydes and Arylamines
under Mild Conditions
Yongzheng Ding, Xian Zhang, Dongyang Zhang, Yuting Chen, Zhibing Wu,
Peiyi Wang, Wei Xue, Baoan Song, Song Yang
PII:
S0040-4039(14)02191-1
DOI:
http://dx.doi.org/10.1016/j.tetlet.2014.12.113
TETL 45638
Reference:
Tetrahedron Letters
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Received Date:
Revised Date:
Accepted Date:
18 September 2014
15 December 2014
21 December 2014
Please cite this article as: Ding, Y., Zhang, X., Zhang, D., Chen, Y., Wu, Z., Wang, P., Xue, W., Song, B., Yang,
S., Copper-Catalyzed Oxidative Amidation between Aldehydes and Arylamines under Mild Conditions,
Tetrahedron Letters (2014), doi: http://dx.doi.org/10.1016/j.tetlet.2014.12.113
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Copper-Catalyzed Oxidative Amidation
between Aldehydes and Arylamines under
Mild Conditions
Leave this area blank for abstract info.
Yongzheng Ding †, Xian Zhang †, Dongyang Zhang, Yuting Chen, Zhibing Wu, Peiyi Wang, Wei Xue, Baoan
Song *, Song Yang ∗

1
Tetrahedron Letters
journal homepage: www.els evier.com
Copper-Catalyzed Oxidative Amidation between Aldehydes and Arylamines under
Mild Conditions
Yongzheng Ding †, Xian Zhang †, Dongyang Zhang, Yuting Chen, Zhibing Wu, Peiyi Wang, Wei Xue,
Baoan Song *, Song Yang *
State Key Laboratory Breeding Base of Green Pesticide and Agricultural Bioengineering, Key Laboratory of Green Pesticide and Agricultural Bioengineering,
Ministry of Education, Center for R&D of Fine Chemicals of Guizhou University, Guiyang, Huaxi District, 550025, P. R. China
*Corresponding Author Emails: jhzx.msm@gmail.com; songbaoan22@yahoo.com.
Tel: +86(851)829-2171, Fax: +86(851)829-2170.
† Both authors contribute equally to this work.
ARTICLE INFO
ABSTRACT
Article history:
Received
A facile strategy to prepare amide bonds has been developed. A series of amide compounds,
including heterocyclic amide compounds, were obtained with moderate to good yields ranging
from 31%–88% by using copper iodide (CuI) to catalyze the oxidative amidation between
aldehydes and amines under solvent-free conditions at room temperature in air.
Received in revised form
Accepted
Available online
2014 Elsevier Ltd. All rights reserved.
Keywords:
Amide bond
Copper catalyst
Oxidative amidation
Solvent-free
Room temperature
Introduction
Even though these metal-catalyzed methods have become
more efficient and more economical for amide bond synthesis,
The synthesis of amide bonds has received extensive
attention because of its powerful applications in agrochemicals,
pharmaceuticals and biomolecules.1 Considerable efforts have
been exerted to develop new and facile strategies to obtain amide
bonds, such as conventional substitution of amines with
carboxylic acids, esters, or acyl halides,2 coupling of carboxylic
acids with isonitriles under suitable microwave thermolytic
conditions,3 coupling of arylalkynes with amines via a series of
oxidants,4 and oxidative amidation of aldehydes or alcohols with
amines at high temperature.5 Furthermore, many classical name
reactions (e.g., Beckmann,6 Staudinger,7 Ugi,8 Ritter reaction,9
etc.) have also been developed to create amide compounds. As a
novel method for preparing amide bonds, the metal-catalyzed
formation of amide bonds has attracted great interest not only
because of its high efficiency and selectivity but also because of
its ease in preparation. Li and co-workers reported a method by
using copper to catalyze the oxidative amidation between
aldehydes and aliphatic amine hydrochloride salts, and this
method achieved good yields when the reaction was performed
by introducing a base.10 Chen and co-workers presented an
approach to synthesize secondary and tertiary amides by using
inexpensive CuSO4·5H2O as the catalyst for the oxidative
amidation of aldehydes with amine hydrochloride salts.11 In
addition, various metals such as Fe,12 Zn,13 Pd,14 and Ru15 were
selected to catalyze the amidation between aldehydes and amines
to develop this methodology.
the pretreatment of amines and the preparation of catalysts are
still time-consuming and complex.16–19 To develop a facile
strategy to obtain amide compounds, copper was used in the
present study as a catalyst to explore the oxidative amidation
between aldehydes and arylamines under solvent-free conditions
at room temperature in air.
Results and discussion
Benzaldehyde and p-toluidine reaction was chosen as a model
to investigate the conditions for the synthesis of N-(p-
tolyl)benzamide. As a general protocol, an aqueous solution of
70% tert-butyl hydroperoxide (TBHP, 1 mmol) was added into a
mixture of benzaldehyde (1 mmol), p-toluidine (0.8 mmol), and
copper catalyst (0.08 mmol) in N2 atmosphere. After stirring for
12 h at room temperature, the mixture was washed with saturated
Na2CO3 aqueous solution, extracted by EtOAc, and further
purified via column chromatography on silica gel to afford the
final amide products (Table 1, entries 1–7). Studies on the
selection of the best catalyst were first performed in the reaction
with various copper salts such as Cu(OAc)2·H2O, CuSO4·5H2O,
Cu(NO3)2·3H2O, CuBr2, CuCl, CuBr, and CuI (entries 1–7). Only
CuI gave a relatively high yield of 57%, thereby indicating that it
has a good catalytic ability to facilitate the formation of the
amide bonds. To compare with CuI catalyst, various oxidants like
H2O2, di-tert-butyl peroxide (DTBP), benzoyl peroxide (BP),
K2S2O8, I2, and air were chosen to optimize the reaction

2
Tetrahedron letters
conditions. However, none of them could give a better yield
f benzaldehyde (2.4 mmol), TBHP (2.4 mmol), r.t., N2 atmosphere.
g benzaldehyde (2.4 mmol), TBHP (2.4 mmol), r.t., air atmosphere.
h benzaldehyde (1.6 mmol), TBHP (2.4 mmol), r.t., air atmosphere.
i benzaldehyde (3.2 mmol), TBHP (2.4 mmol), r.t., air atmosphere.
(entries 8–13). The results suggested that TBHP has high
efficiency to promote amidation in this reaction. Furthermore,
control experiments (entries 14, 15) revealed that both CuI and
TBHP were necessary components in the formation of the amide
bonds. To determine whether TBHP concentration affects the
yield of the amide products, various concentrations were tested.
The yield of the final amide compounds reach 65% when the
dosage of TBHP was increased to 2.4 mmol in N2 atmosphere
(entries 16, 17). Furthermore, the yield was not significantly
affected when the reaction was carried out in air atmosphere
(entry 18). Further optimization revealed that the amide product
of this reaction could be obtained with a good yield of 69% when
the dosage of benzaldehyde was up to three times that of p-
toluidine in air atmosphere (entries 18–20). Based on the above
results, the conditions of entry 18 were chosen for further studies.
With the given optimized conditions, the copper-catalyzed
amidation was performed and examined using a series of
aldehydes and amines. As shown in Table 2, when the substituted
anilines reacted with aromatic aldehydes, moderate to good
yields of amides ranging from 43%–88% (3a–3e) were obtained.
By contrast, the yield decreased when the aromatic aldehydes
were changed into aliphatic aldehydes (3m–3p). Specific
heterocyclic amide compounds perform extremely important
functions in medicine,20 fungicide,21 and insecticide.22 To extend
our method for potential applications, the preparation of amides
from heterocyclic amines or heterocyclic aldehydes were also
examined, and all of them could be converted into their
corresponding amides with acceptable yields under the same
conditions (3f–3m). By comparison, aliphatic amines exhibited
excellent reactivity with aromatic aldehyde, resulting in 88% and
84% yields, respectively (3q, 3r).
Table 1. Optimization of reaction conditions.a
Table 2. Amidation of aldehydes with amines.a
Entry
1
Catalyst
Oxidation
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Yield (%)b
trace
n.d.c
26
Cu(OAc)2·H2O
2
CuSO4·5H2O
O
3
Cu(NO3)2·3H2O
N
H
4
CuBr2
CuCl
CuBr
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
/
34
3a, 69%
3d, 73%
3b, 88%
3e, 43%
3c, 65%
3f, 61%
5
21
6
30
7
57
d
8
H2O2
7
9
DTBP
BP
trace
19
10
11
12
13
14
15
16e
17f
18g
19h
20i
K2S2O8
I2
trace
n.d.
n.d.
n.d.
n.d.
59
3g, 42%
3j, 60%
3h, 45%
3k, 31%
3i, 49%
3l, 81%
Air
/
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
CuI
CuI
CuI
CuI
CuI
65
3m, 45%
3n, 44%
3o, 34%
69
60
70
a
Reaction conditions: benzaldehyde (1.0 mmol), p-toluidine (0.8 mmol),
catalyst (0.08 mmol), 70% aq. TBHP (1.0 mmol), solvent-free, r.t., 12 h, N2
atmosphere.
3p, 45%
a
3q, 88%
3r, 84%
Reaction conditions: aldehyde (2.4 mmol), amine (0.8 mmol), CuI (0.08
mmol), 70% aq. TBHP (2.4 mmol), solvent-free, r.t., 12 h, air atmosphere.
b isolated yield.
In this system, the possible intermediates might be imines,
carboxylic acids, or hemiaminals.18 To elucidate the reaction
mechanism, two control experiments were performed. As shown
in Scheme 1, the possible intermediate imine or carboxylic acid
c n.d. = not detected
d 30% aqueous solution.
e benzaldehyde (2.4 mmol), TBHP (1.2 mmol), r.t., N2 atmosphere

3
A.; Skaptason, J.; Yamazaki, S.; Neul, D.; Zientek, M.; Elleraas, J.;
was used as reagent to explore oxidative amidation at standard
conditions. However, none of them resulted in a good yield,
indicating that neither imine nor carboxylic acid was the main
intermediate in this reaction. Based on the above results and the
known literature,10, 18 a proposed pathway is shown in Scheme 2.
However, all attempts to obtain hemiaminal intermediates failed,
probably because of its unstable nature.
Mehta, P.; Yin, M. J.; Hickey, M. J.; Gajiwala, K. S.; Rodgers, C.;
Davies, J. F.; Gehring, M. R. J. Med. Chem. 2010, 53, 499-503; (c)
Cupido, T.; Tulla-Puche, J.; Spengler, J.; Albericio, F. Curr. Opin. Drug
Discovery Dev. 2007, 10, 768-783; (d) Bode, J. W. Curr. Opin. Drug
Discovery Dev. 2006, 9, 765-775; (e) Humphrey, J. M.; Chamberlin, A.
R. Chem. Rev. 1997, 97, 2243-2266.
2.
3.
Valeur, E.; Bradley, M. Chem. Soc. Rev. 2009, 38, 606-631.
(a) Wu, X. Y.; Stockdill, J. L.; Wang, P.; Danishefsky, S. J. J. Am.
Chem. Soc. 2010, 132, 4098-4100; (b) Li, X. C.; Danishefsky, S. J. J.
Am. Chem. Soc. 2008, 130, 5446-5448; (c) Li, X. C.; Yuan, Y.;
Berkowitz, W. F.; Todaro, L. J.; Danishefsky, S. J. J. Am. Chem. Soc.
2008, 130, 13222-13224; (d) Li, X. C.; Yuan, Y.; Kan, C.; Danishefsky,
S. J. J. Am. Chem. Soc. 2008, 130, 13225-13227; (e) Wu, X. Y.; Li, X.
C.; Danishefsky, S. J. Tetrahedron Lett. 2009, 50, 1523-1525; (f) Li, X.
C.; Danishefsky, S. J. Nat. Protoc. 2008, 3, 1666-1670.
O
CH=N
standard conditions
N
H
yield: 9%
O
COOH
standard conditions
N
H
4.
5.
Chan, W. K.; Ho, C. M.; Wong, M. K.; Che, C. M. J. Am. Chem. Soc.
2006, 128, 14796-14797.
+
H2N
not detected
(a) Wang, Y.; Zhu, D. P.; Tang, L.; Wang, S. J.; Wang, Z. Y. Angew.
Chem. Int. Ed. 2011, 50, 8917-8921; (b) Reddy, K. R.; Maheswari, C.
U.; Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 2008,
3619-3622; (c) Wu, X. F.; Sharif, M.; Pews-Davtyan, A.; Langer, P.;
Ayub, K.; Beller, M. Eur. J. Org. Chem. 2013, 2783-2787; (d) Kegnæs,
S.; Mielby, J.; Mentzel, U. V.; Jensen, T.; Fristrup, P.; Riisager, A.
Chem. Commun. 2012, 48, 2427-2429; (e) Gunanathan, C.; Ben-David,
Y.; Milstein, D. Science 2007, 317, 790-792.
Scheme 1. Experiments for the mechanism of amidation.
OH
O
O
[Cu]
[O]
R2
+
H2N R2
R2
R1
N
H
R1
N
H
R1
H
6.
7.
(a) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9,
3599-3601; (b) Hashimoto, M.; Obora, Y.; Sakaguchi, S.; Ishii, Y. J.
Org. Chem. 2008, 73, 2894-2897.
Scheme 2. Possible pathway of amidation between aldehydes and
amines
(a) Damkaci, F.; DeShong, P. J. Am. Chem. Soc. 2003, 125, 4408-4409;
(b) Saxon, E.; Bertozzi, C. R. Science 2000, 287, 2007-2010; (c)
Gololobov, Y. G.; Kasukhin, L. F. Tetrahedron 1992, 48, 1353-1406.
Ugi, I. Angew. Chem. Int. Ed. 1962, 1, 8-21.
Conclusions
8.
9.
In summary, a strategy to prepare amide compounds was
developed by using copper iodide to catalyze the oxidative
amidation between aldehydes and arylamines under solvent-free
conditions at room temperature in air. Meanwhile, the synthetic
conditions were investigated and optimized. When different
amines were reacted with various aldehydes, a series of amide
compounds, including heterocyclic amides, were obtained with
moderate to good yields ranging from 31%–88%. Finally, a
possible reaction pathway was proposed. This facile method can
be used in the synthesis of agrochemicals, pharmaceuticals, and
novel biomolecules.
Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045-4048.
10. Yoo, W. J.; Li, C. J. J. Am. Chem. Soc. 2006, 128, 13064-13065.
11. Ghosh, S. C.; Ngiam, J. S. Y.; Seayad, A. M.; Tuan, D. T.; Chai, C. L.
L.; Chen, A. Q. J. Org. Chem. 2012, 77, 8007-8015.
12. Ghosh, S. C.; Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T.
T.; Chen, A. Q. Adv. Synth. Catal. 2012, 354, 1407-1412.
13. Zhang, M.; Wu, X. F. Tetrahedron Lett. 2013, 54, 1059-1062.
14. Suto, Y.; Yamagiwa, N.; Torisawa, Y. Tetrahedron Lett. 2008, 49,
5732-5735.
15. Naota, T.; Murahashi, S. I. Synlett 1991, 1991, 693-694.
16. (a) Seo, S. Y.; Marks, T. J. Org. Lett. 2008, 10, 317-319; (b) Qian, C.
W.; Zhang, X. M.; Li, J. M.; Xu, F.; Zhang, Y.; Shen, Q.
Organometallics 2009, 28, 3856-3862; (c) Cai, C. Y.; Li, L.; Xu, F.;
Shen, Q. Chinese Sci. Bull. 2010, 55, 3641-3643; (d) Qian, C. W.;
Zhang, X. M.; Zhang, Y.; Shen, Q. J. Organomet. Chem. 2010, 695,
747-752; (e) Wu, Y. J.; Wang, S. W.; Zhang, L. J.; Yang, G. S.; Zhu, X.
C.; Zhou, Z. H.; Zhu, H.; Wu, S. H. Eur. J. Org. Chem. 2010, 326-332;
(f) Li, J. M.; Xu, F.; Zhang, Y.; Shen, Q. J. Org. Chem. 2009, 74, 2575-
2577; (g) Xu, B.; Huang, L. L.; Yang, Z. J.; Yao, Y. M.; Zhang, Y.;
Shen, Q. Organometallics 2011, 30, 3588-3595.
Acknowledgments
This work was supported by the National Natural Science
Foundation of China (21372052), Key Technologies R&D
Program (2011BAE06B02-23), and the Graduate Student
Innovation Foundation of Guizhou University (2014077,
2014078).
17. Thomson, J. A.; Schafer, L. L. Dalton Trans. 2012, 41, 7897-7904.
18. Gao, J.; Wang, G. W. J. Org. Chem. 2008, 73, 2955-2958.
19. Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429-3432.
20. (a) White, A. D.; Purchase, II, C. F.; Picard, J. A.; Anderson, M. K.;
Mueller, S. B.; Bocan, T. M.; Bousley, R. F.; Hamelehle, K. L.; Krause,
B. R.; Lee, P.; Stanfield, R. L.; Reindel, J. F. J. Med. Chem. 1996, 39,
3908-3919; (b) Ramurthy, S.; Costales, A.; Jansen, J. M.; Levine, B.;
Renhowe, P. A.; Shafer, C. M.; Subramanian, S. Bioorg. Med. Chem.
Lett. 2012, 22, 1678-1681.
Supplementary data
Experimental section; General procedures; Experimental
characterization data of 3a–3r; 1H NMR and 13C NMR spectra of
3a–3r (Figures S1~S36). This material is available free of charge
via the internet at http://www.sciencedirect.com/.
21. (a) Wu, Z. B.; Hu, D. Y.; Kuang, J. Q.; Cai, H.; Wu, S. X.; Xue, W.
Molecules 2012, 17, 14205-14218; (b) Yang, J. C.; Zhang, J. B.; Chai,
B. S.; Liu, C. L. Nongyao, 2008, 47, 6-9, (in Chinese).
22. Wang, J.; Luo, M.; Hu, C. Y.; Sun, D. Y. Asian J. Chem. 2014, 26, 311-
312.
References and notes
1.
(a) Pattabiraman, V. R.; Bode, J. W. Nature 2011, 480, 471-479; (b)
Kung, P. P.; Huang, B. W.; Zhang, G.; Zhou, J. Z.; Wang, J.; Digits, J.