The copper-catalyzed aerobic oxidative amidation of tertiary amines

Article abstract of DOI:10.1039/c5cc07454a

A general and efficient method for the synthesis of tertiary amides has been developed via the copper-catalyzed aerobic oxidative amidation of tertiary amines. Due to the use of the O₂ oxidant, various functional groups were well tolerated under the present conditions. Extensive substrates studies demonstrated its potential as a practical approach for the synthesis of tertiary amides.

Full text of DOI:10.1039/c5cc07454a

View Article Online
View Journal
ChemComm
Accepted Manuscript
This article can be cited before page numbers have been issued, to do this please use: H. Cheng, W.
Hou, Z. Li, M. Liu and B. Guan, Chem. Commun., 2015, DOI: 10.1039/C5CC07454A.
This is an Accepted Manuscript, which has been through the
Royal Society of Chemistry peer review process and has been
accepted for publication.
Accepted Manuscripts are published online shortly after
acceptance, before technical editing, formatting and proof reading.
Using this free service, authors can make their results available
to the community, in citable form, before we publish the edited
article. We will replace this Accepted Manuscript with the edited
and formatted Advance Article as soon as it is available.
You can find more information about Accepted Manuscripts in the
Information for Authors.
Please note that technical editing may introduce minor changes
to the text and/or graphics, which may alter content. The journal’s
standard Terms & Conditions and the Ethical guidelines still
apply. In no event shall the Royal Society of Chemistry be held
responsible for any errors or omissions in this Accepted Manuscript
or any consequences arising from the use of any information it
contains.
www.rsc.org/chemcomm

Please do not adjust margins
ChemComm
Page 1 of 4
View Article Online
DOI: 10.1039/C5CC07454A
Journal Name
COMMUNICATION
Copper‐Catalyzed Aerobic Oxidative Amidation of Tertiary Amines
Hui‐Cheng Cheng, Wen‐Jun Hou, Zeng‐Wen Li, Ming‐Yu Liu and Bing‐Tao Guan*
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A general and efficient method for the tertiary amide synthesis
has been developed via copper‐catalyzed aerobic oxidative
amidation of tertiary amines. Due to the use of O2 oxidant, various
functional groups were well tolerated under present conditions.
Extensive substrates studies demonstrated its potential as a
practical approach for the tertiary amide synthesis.
Amides as an important structure unit exist widely in natural
products, biological compounds, pharmaceuticals and
synthetic materials.1 Therefore, the development of amides
synthesis has attracted much attention and has been
extensively studied.2 Traditionally, amide is synthesized by the
amidation of primary and secondary amines. Due to the
reactivity of the amines and amides, the protection and
deprotection processes are always necessary in a multistep
synthesis, which would undoubtedly compromise their
synthetic efficiency. Generally, tertiary amines are easily
available and stable enough to survive under many conditions.
So the amides synthesis via tertiary amines amidation could
provide an ideal late stage synthetic approach.3
Scheme 1. Catalytic Oxidative Amidation of Tertiary Amines.
recently proved their powerful ability in the aerobic oxidative
transformations.10 Herein, we report a general and efficient
protocol for the aerobic amidation of tertiary amines. The
good efficiency, selectivity and function group tolerance make
it a possible candidate as an ideal late stage amidation
reaction.
Initially, we investigated the catalytic efficiency of several
catalysts using N,N‐dimethylaniline and acetic anhydride as
substrates in refluxing acetonitrile under O2 atmosphere. The
The easy oxidative reactivity4 enables tertiary amines to
undergo efficient amidation reactions in the presence of
oxidants such as peroxides [Scheme 1, eqn (2)].5, 6 The use of
those oxidants would definitely lead to poor function group
tolerance from a synthetic point of view. The aerobic oxidative
amidation of tertiary amines was reported in 1990s by Miura
and coworkers with Co or Cu catalysts.7 However, the
substrates were greatly limited to 4‐substituted aniIines
[Scheme 1, eqn (1)]. The aerobic amidation of tertiary amines
were further developed with various catalysts in conjugation
with various acylation reagents.8 Those methods reported so
far suffered from limited substrate scope and poor selectivity.
The use of molecular oxygen as an ideal oxidant for organic
synthesis has drawn much attention.9 The copper catalysts had
Cu, Co and Fe salts which successfully catalyzed the aerobic
8e
amidation of 4‐substituted aniIines7,
failed to drive the
amidation of N,N‐dimethylaniline efficiently (Table 1, entries 1‐
3). Cu(OAc)2 was found to be a suitable catalyst and N‐methyl‐
N‐phenylacetamide 3a was obtained in the yield of 88% after
refluxing in MeCN for 36 hours (Table 1, entry 6). Shorter
reaction time or lower temperature would lead to the drop of
the yields (Table 1, entries 7‐8). Blank experiments were
carried out, and the reaction could not take place without
either Cu(OAc)2 catalyst or O2 atmosphere (Table 1, entries 9‐
10). The catalytic aerobic amidation could even take place in
air, and a comparable yield was obtained with longer time
(Table 1, entries 11‐12). The efficiency of the catalytic aerobic
amidation reaction was related much to the amount of the
acetic anhydride: 3 equivalent of acetic anhydride or more
would give comfortable yields, while less amount of the acetic
State Key Laboratory and Institute of Elemento‐Organic Chemistry, Collaborative
Innovation Center of Chemical Science and Engineering, Nankai University, Tianjin
300071 (China). E‐mail: guan@nankai.edu.cn
Electronic Supplementary Information (ESI) available: General procedures,
experimental details, and NMR‐spectra. See DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 1
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 2 of 4
COMMUNICATION
Journal Name
View Article Online
DOI: 10.1039/C5CC07454A
Table 1. Catalytic Aerobic Oxidative Acetylamination of
N,N‐Dimethylaniline.
O
catalyst
+
Ac2O
N
N
Ac
Ac
Ac
Ac
solvent, O2 baloon
N
N
N
N
1a
2a
3a
Me
MeO
MeO2C
MeO2C
Entrya
Catalyst
CuCl
Solvent
CH3CN
Temp.
reflux
reflux
reflux
reflux
reflux
reflux
reflux
60 ºC
reflux
reflux
reflux
reflux
reflux
reflux
100 ºC
100 ºC
Time
36
36
36
36
36
36
24
36
36
36
36
72
36
36
36
36
Yield 3ab
3b, 83%
3c, 89%
3d, 89%
Ac
3e, 70%a
Ac
Ac
Ac
Ac
1
2
40%
N
N
N
N
N
CoCl2
FeCl3
CuCl2
CuBr2
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
toluene
DMSO
7%
NC
OHC
Ac
F3C
O2N
3f, 82%a
3g, 52%b
3h, 85%b
3i, 60%b
3j, 50%b
3
5%
Ac
Ac
Ac
Ac
Ac
4
25%
N
N
N
N
N
5
57%
F3C
O
O
Ac
3k, 72%a
Ac
Ac
3l, 89%a
OAc
3m, 96%b
CO2Me
CON(Pri)2
3o, 80%a
6
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
--
88%
3n, 85%
7
76%
Me Ac
Me Ac
Br Ac
SMe Ac
Cl
N
N
N
N
N
8
32%
Me
9
<5%
3p, 85%b
3q, 70%a
3r, 84%b
3s, 90%a
3t, 86%b
10c
11d
12d
13e
14f
15
16
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
<5%
Scheme 2 Scope of substituted N,N‐dimethylanilines.
45%
Conditions: Aniline (0.5 mmol), Ac2O (3.0 equiv), Cu(OAc)2
(5 mol %), MeCN (1 maL), O2 balloon, reflux, 36 hours,
86%
b
isolated yields reported. Ac2O: 10 equiv. 2 mL of Ac2O,
no MeCN, 100
℃.
60%
94% (90%)
14%
products in fair to good yields if only under more concentrated
acetic anhydride conditions (3e ). 4‐(Dimethylamino)‐phenol
and 2,2,2‐trifluoro‐1‐(4‐(dimethylamino)phenyl)ethanol could
‐
j
11%
also undergo the amidation reaction with the hydroxyl groups
acetylized at the same time (3k‐l). N,N‐Dimethylanilines with
substituted group at meta‐ or ortho‐position were reacted
with acetic anhydride, and the corresponding products were
a
Conditions: N,N‐dimethylaniline 1a (0.5 mmol), Ac2O
(3.0 equiv), catalyst (5 mol %), MeCN (1 mL), O2 balloon,
reflux, 36 hours; unless otherwise noted; b GC yields with
tridecane as internal standard and isolated yield in
parenthesis. Under argon. Under air. 2.0 equiv.
f Ac2O: 5.0 equiv.
obtained in good to excellent yields (3m
note that the steric hindered substrates smoothly underwent
the aerobic amidation reaction 3q ). Moreover, the
‐t). It is interesting to
c
d
e
(
‐t
anhydride gave a lower yield (Table 1, entries 13‐14). Several methylthio group well survived the oxidative condition (3t).
solvents were tested in the reaction, and MeCN proved to be
N,N‐Dimethyl‐2‐naphthylamine smoothly reacted with
the solvent of choice (Table 1, entries 15‐16).
acetic anhydride, and gave the amidation product in excellent
Under these optimized conditions, various substituted yield (Scheme 3, 4a). Not only the N‐Me bonds containing
tertiary anilines were subjected to the catalytic aerobic anilines but also the other N‐alkyl compounds could serve as
acetylamination reaction (Scheme 2). para‐Methyl and substrates for the aerobic oxidative amidation reaction. The
methoxy‐N,N‐dimethylaniline gave amidation products in good reaction between N,N‐diethylaniline and acetic anhydride gave
yields under present conditions
(3b‐c). Methyl 4‐ N‐ethyl‐N‐phenylacetamide
(4b) in yield of 94%. The
dimethylaminocinnamate smoothly reacted with acetic unsymmetrical anilines such as N‐ethyl‐N‐methylaniline and N‐
anhydride to afford desired amidation product with the methyl benzyl‐N‐methylaniline gave a mixture of N‐phenylacetamides
cinnamate part intact (3d). Electron‐withdrawing groups on with nice selectivity (4b and 3a
, 4c and 3a). Compared with
anilines would reduce the electron density and suppress the ethyl and benzyl group, methyl group showed much better
oxidative reactions. Hence, the anilines with electron‐ reactivity.11 Beside anilines, alkyl amines could also undergo
withdrawing groups were seldom reported to undergo the the aerobic oxidative amidation reaction: either N‐Me bond of
aerobic oxidative amidation reaction. For the efficiency of the dicyclohexylmethylamine or N‐Bu bond of tributylamine were
present method, the anilines bearing electron‐withdrawing converted to acetamide groups (4d
‐e). Notably, a wide range
groups such as cyano, methoxycarbonyl, formyl, acyl, of heterocycles were also compatible with this protocol.
trifluoromethyl and even nitro group could afford amidation Tertiary amines bearing heterocycles such as pyridine,
2 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 3 of 4
Journal Name
COMMUNICATION
View Article Online
DOI: 10.1039/C5CC07454A
Scheme 4. Scope of anhydrides. Conditions: 2‐
Phenylaniline (0.5 mmol), anhydride (3.0 equiv), Cu(OAc)2
(5 mol %), MeCN (1 mL), O2 balloon, reflux, 36 hours,
a
isolated yields reported. Benzoic acid (3.0 equiv) and
pivalic anhydride (3.0 equiv) instead of benzoic anhydride.
b 2‐phenoxyacetic anhydride: 5.0 equiv.
Scheme 3. Scope of tertiary amines. Conditions: tertiary
amine (0.5 mmol), Acetic anhydride (3.0 equiv), Cu(OAc)2
(5 mol%), MeCN (1 mL), O2 balloon, reflux, 36 hours,
a
isolated yields reported; unless otherwise noted. Ac2O:
10 equiv. b 2 mL of Ac2O, no MeCN, 85
byproduct. d NMR ratio.
℃
. c Formyl amide
Scheme 5. Synthetic application. Conditions: [a] CH3MgCl
(2.0 equiv), THF, rt, 2 hours; [b] Compound 6 (0.5 mmol),
anhydride (10.0 equiv), Cu(OAc)2 (5 mol %), MeCN (1 mL),
O2 balloon, reflux, 36 hours.
quinoline, thiophene and benzothiazol underwent the aerobic
oxidative amidation reaction smoothly, and gave desired
products in moderate yields (4f‐i).
To examine the scope of anhydrides further, N,N‐dimethyl‐
2‐phenylaniline was allowed to react with various anhydrides
(Scheme 4). With the increase of the steric hindrance of the
anhydrides, the yields of the amidation products tended to
decline under similar conditions (5a‐d). The pivalic anhydride
completely failed to drive the aerobic amidation reaction.
Chloride or a phenoxy group substituted acetic anhydride
reacted with N,N‐dimethyl‐2‐phenylaniline smoothly, and the
amidation products were obtained in moderate yields (5e‐f).
Moreover, benzoic anhydride was subjected to the aerobic
oxidative amidation, and the benzamide product (5g) was
produced in 84% yield. Instead of benzoic anhydride, the
mixture of benzoic acid and pivalic anhydride could also serve
as the benzoylation reagent to afford 5g in 75% yield.
In summary, we have developed a general and practical
method for the tertiary amide synthesis via copper‐catalyzed
aerobic oxidative amidation of tertiary amines. For the easily
available substrates, mild conditions, and good functional
group compatibility, this process could potentially offer a
practical approach for the tertiary amide synthesis.
Acknowledgements
This Project was supported by the NSFC (21202086,
21372123), and the Natural Science Foundation of Tianjin
(13JCYBJC40900). We gratefully acknowledge the State Key
Laboratory of Elemento‐Organic Chemistry for generous start‐
up financial support.
As an important small‐molecule MCD inhibitor, compound
5h was synthesized by the amidation of the secondary
aniline.12 Starting from its tertiary analogue, the aerobic
oxidative amidation could give compound 5h in yield of 72%.
Notes and references
The hexafluoroisopropanol moiety well survived under present 1. (a) A. Greenberg, C. M. Breneman and J. F. Liebman, The amide
linkage: selected structural aspects in chemistry, biochemistry, and
materials science, Wiley‐Interscience, New York, 2000. (b) J. M.
Humphrey and A. R. Chamberlin, Chem. Rev., 1997, 97, 2243.
2. (a) R. C. Larock, Comprehensive organic transformations: a
guide to functional group preparations, Wiley‐VCH, New York, 1999.
(b) C. Nájera, Synlett, 2002, 1388; (c) S. Han and Y. Kim, Tetrahedron,
2004, 60, 2447; (d) F. Albericio, Curr. Opin. Chem. Biol., 2004, 8, 211;
(e) E. Valeur and M. Bradley, Chem. Soc. Rev., 2009, 38, 606; (f) C. L.
Allen and J. M. J. Williams, Chem. Soc. Rev., 2011, 40, 3405; (g) V. R.
Pattabiraman and J. W. Bode, Nature, 2011, 480, 471; (h) S. Roy, S.
Roy and G. W. Gribble, Tetrahedron, 2012, 68, 9867;.
conditions. To further demonstrate the generality and
practicality of the aerobic oxidative amidation, we proposed to
synthesize another MCD inhibitor candidate
7 (Scheme 5),
which was prepared via multiple‐step reactions such as
amidation, alkylation, oxidation and addition reactions.12b The
easily available starting material trifluoroacetyl aniline could
undergo the addition reaction with methyl magnesium
chloride under mild condition to give compound
yield. Then the aerobic oxidative amidation was carried out to
afford the desired product in 74% yield.
6 in a high
7
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1‐3 | 3
Please do not adjust margins

Please do not adjust margins
ChemComm
Page 4 of 4
COMMUNICATION
Journal Name
3. (a) R. P. Mariella and K. H. Brown, Can. J. Chem., 1971, 49, 3348; Arrhenius and A. M. Nadzan, Bioorg. Med. Chem. Lett., 2007, 17,
View Article Online
(b) B. T. Khai and A. Arcelli, J. Organomet. Chem., 1983, 252, c9; (c) J. 1127.
H. Cooley and E. J. Evain, Synthesis, 1989, 1.
DOI: 10.1039/C5CC07454A
4. The oxidative transformations of tertiary amines play vital roles
in biochemistry and chemistry. (a) J. W. Gorrod and L. A. Damani,
Biological oxidation of nitrogen in organic molecules: chemistry,
toxicology, and pharmacology, VCH, Weinheim, Federal Republic of
Germany, 1985. (b) P. R. Ortiz de Montellano, Cytochrome P‐450:
structure, mechanism, and biochemistry, Plenum Press, New York,
1986. (c) S. Murahashi, Angew. Chem. Inter. Ed., 1995, 34, 2443; (d)
S. Murahashi and D. Zhang, Chem. Soc. Rev., 2008, 37, 1490.
5. (a) D. Grierson, in Organic Reactions, John Wiley & Sons, Inc.,
New York, 2004. (b) Y. Li, F. Jia and Z. Li, Chem. Eur. J., 2013, 19, 82;
(c) Y. Li, L. Ma, F. Jia and Z. Li, J. Org. Chem., 2013, 78, 5638; (d) W.
Mai, G. Song, J. Yuan, L. Yang, G. Sun, Y. Xiao, P. Mao and L. Qu, RSC
Adv., 2013, 3, 3869; (e) X. Zhang, W. Yang and L. Wang, Org. Biomol.
Chem., 2013, 11, 3649.
6. (a) B. Rindone and C. Scolastico, Tetrahedron Lett., 1974, 15,
3379; (b) G. Galliani, B. Rindone and C. Scolastico, Tetrahedron Lett.,
1975, 16, 1285; (c) G. Galliani, B. Rindone and P. L. Beltrame, J.
Chem. Soc., Perkin Trans. 2, 1976, 1803; (d) G. Galliani and B.
Rindone, J. Chem. Soc., Perkin Trans. 1, 1980, 828; (e) T. Santa, N.
Miyata and M. Hirobe, Chem. Pharm. Bull., 1984, 32, 1252; (f) B.
Xiong, L. Zhu, X. Feng, J. Lei, T. Chen, Y. Zhou, L. Han, C. Au and S.
Yin, Eur. J. Org. Chem., 2014, 4244.
7. (a) S. Murata, A. Tamatani, K. Suzuki, M. Miura and M. Nomura,
Chem. Lett., 1990, 19, 757; (b) S. Murata, K. Suzuki, A. Tamatani, M.
Miura and M. Nomura, J. Chem. Soc., Perkin Trans. 1, 1992, 1387.
8. (a) R. J. Carroll, H. Leisch, E. Scocchera, T. Hudlicky and D. P. Cox,
Adv. Synth. Catal., 2008, 350, 2984; (b) A. Machara, D. P. Cox and T.
Hudlicky, Adv. Synth. Catal., 2012, 354, 2713; (c) Y. Bao, B.
Zhaorigetu, B. Agula, M. Baiyin and M. Jia, J. Org. Chem., 2014, 79,
803; (d) X. Chen, T. Chen, Q. Li, Y. Zhou, L. Han and S. Yin, Chem. Eur.
J., 2014, 20, 12234; (e) L. Ma, Y. Li and Z. Li, Sci. China. Chem., 2015,
58, 1310.
9. (a) T. Punniyamurthy, S. Velusamy and J. Iqbal, Chem. Rev.,
2005, 105, 2329; (b) J. Piera and J. Bäckvall, Angew. Chem. Inter. Ed.,
2008, 47, 3506; (c) Z. Shi, C. Zhang, C. Tang and N. Jiao, Chem. Soc.
Rev., 2012, 41, 3381.
10. (a) J. Piera and J. Bäckvall, Angew. Chem. Inter. Ed., 2008, 47,
3506; (b) S. E. Allen, R. R. Walvoord, R. Padilla‐Salinas and M. C.
Kozlowski, Chem. Rev., 2013, 113, 6234; (c) S. D. McCann and S. S.
Stahl, Accounts Chem. Res., 2015, 48, 1756; (d) K. V. N. Esguerra, Y.
Fall, L. Petitjean and J. Lumb, J. Am. Chem. Soc., 2014, 136, 7662; (e)
K. V. N. Esguerra, Y. Fall and J. Lumb, Angew. Chem. Inter. Ed., 2014,
53, 5877; (f) B. Xu, J. Lumb and B. A. Arndtsen, Angew. Chem. Inter.
Ed., 2015, 54, 4208; (g) Q. Liu, P. Wu, Y. Yang, Z. Zeng, J. Liu, H. Yi
and A. Lei, Angew. Chem. Inter. Ed., 2012, 51, 4666; (h) R. Shi, L. Lu,
H. Zhang, B. Chen, Y. Sha, C. Liu and A. Lei, Angew. Chem. Inter. Ed.,
2013, 52, 10582; (i) J. Liu, X. Zhang, H. Yi, C. Liu, R. Liu, H. Zhang, K.
Zhuo and A. Lei, Angew. Chem. Inter. Ed., 2015, 54, 1261; (j) X.
Huang, X. Li, M. Zou, S. Song, C. Tang, Y. Yuan and N. Jiao, J. Am.
Chem. Soc., 2014, 136, 14858; (k) X. Li, X. Liu, H. Chen, W. Wu, C. Qi
and H. Jiang, Angew. Chem. Inter. Ed., 2014, 53, 14485; (l) S. Guo, B.
Qian, Y. Xie, C. Xia and H. Huang, Org. Lett., 2011, 13, 522.
11. Benzyl group was reported with comparative or better reactivity
in Iron‐catalyzed oxidative amidation of tertiary amines with
peroxide as oxidant: Refs 5b and 5c.
12. (a) J. Cheng, M. Chen, D. Wallace, S. Tith, M. Haramura, B. Liu, C.
C. Mak, T. Arrhenius, S. Reily, S. Brown, V. Thorn, C. Harmon, R. Barr,
J. R. B. Dyck, G. D. Lopaschuk and A. M. Nadzan, J. Med. Chem.,
2006, 49, 1517; (b) D. M. Wallace, M. Haramura, J. Cheng, T.
4 | J. Name., 2012, 00, 1‐3
This journal is © The Royal Society of Chemistry 20xx
Please do not adjust margins