Copper-catalyzed one-pot oxidative amidation of alcohol to amide via C-H activation

Article abstract of DOI:10.1039/c6ra20732d

A one-pot oxidative amidation of both aliphatic and aromatic alcohols with N-chloramines, prepared in situ from many types of primary and secondary amines, was developed. This cross-coupling reaction integrates alcohol oxidation and amide bond formation, which are usually accomplished separately, into a single operation. And it was green, simple and convenient, which has a wide substrate scope and makes use of cheap, abundant, and easily available reagents. The practical value of this method is highlighted through the synthesis of a high-profile pharmaceutical agent, acetylprocainamide.

Full text of DOI:10.1039/c6ra20732d

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COMMUNICATION
Copper-catalyzed one-pot oxidative amidation of alcohol to amide
via C-H activation
Jiajia Gu, a Zheng Fang, *a Yuhang Yang, a Zhao Yang, b Li Wan, a Xin Li, a Ping Wei a and Kai Guo *a, c
Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
www.rsc.org/
A one-pot oxidative amidation of both aliphatic and aromatic alcohols can be a potentially attractive method due to the use
alcohols with N-chloroamines, prepared in situ from many types of cheap, abundant and stable starting materials.8 To date, the
of primary and secondary amines, was developed. This cross- oxidative amidation of alcohols is essentially promoted by
coupling reaction integrates alcohol oxidation and amide bond homogeneous or heterogeneous catalysts, such as Ru- or Rh-
formation, which are usually accomplished separately, into a based transition metal complexes,9 and Ag- or Au-based
single operation. And it was green, simple and convenient, which supported catalysts.10 Usually, these strategies consist of the
has a wide substrate scope and makes use of cheap, abundant, oxidation of an alcohol to the corresponding aldehyde that
and easily available reagents. The practical value of this method is reacts with an amine and then further oxidize the hemiaminal
highlighted through the synthesis of high-profile pharmaceutical to the desired amide (Scheme 1).
agents, acetylprocainamide.
The formation of amide bonds is one of the most often used
organic reactions due to the extensive presence of this
functional group in natural products, pharmaceutical
compounds, and synthetic polymers.1 Conventionally, amides
Scheme 1 Oxidative amidation of alcohols with amines
are synthesized by the reaction of an amine with carboxylic
2
acid, which needs either coupling reagent or conversion into
In order to compete with those techniques involving
more reactive derivatives.3 However, these methods have
expensive metals, studies on zinc- or copper- or iron-catalyzed
several common shortcomings, such as poor atom-efficiency,
oxidative amidation of alcohols have been developed.11-13 In
use of hazardous reagents, and generation of wastes which
2013, Wu et al. reported the zinc-catalyzed oxidative
cause environmental problems. To solve these problems,
amidation of benzyl alcohols (Scheme 2a).11 Similar approach
alternative methods for amide synthesis were developed, such
using copper or iron was developed (Scheme 2b).12, 13 However,
as name reactions like the Schmidt reaction,4 the Beckmann
these methods have several drawbacks, such as the formation
rearrangement,5 and Ugi reaction.6 More recent approach has
and stability of the hemiaminal intermediate, the use of
considered the use of direct oxidative amidation from
expensive transition metal catalysts, and the limited substrate
aldehydes.7 However, these methods require the use of
scope. Therefore, it remains a great challenge to develop new
expensive transition metals as catalyst, and the use of
methods to synthesis amide. The direct conversion of C-H
aldehydes can be troublesome due to their inherent reactivity.
bonds into C-N bonds appears to be a critical but appealing
From the recent perspective of green chemistry, it remains a
14
15
challenge in organic chemistry. Recently, Wan and Wang
great challenge to develop a general and efficient method for
the synthesis of amide. The direct oxidative amidation of
reported the formation of C-N bond via C-H aldehyde bond
activation. In 2013, Gaspa et al. used this method to develop
the iron-catalyzed amidation of N-chloramines, prepared from
amine, which needed the use of 5 equiv of alcohols to obtain
a.College of Biotechnology and Pharmaceutical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
16
good yields (Scheme 2c). However, these methods outlined
b.School of Engineering, China Pharmaceutical University, No.639 Longmian
Avenue, Nanjing 211198, China.
above shared a common drawback, which was that they
showed excellent activity only with benzyl alcohols. Aliphatic
alcohols did not perform well in their system. Herein, we
report an efficient and green one-pot procedure for the direct
amidation of both aliphatic and aromatic alcohols with N-
c. State Key Laboratory of Materials-Oriented Chemical Engineering, Nanjing Tech
University, 30 Puzhu Rd S., Nanjing 211816, China.
Email: guok@njtech.edu.cn, fzcpu@163.com, Tel +86 25 5813 9926, Fax +86 25
5813 9935.
Electronic Supplementary Information (ESI) available: [Copies of 1H and 13C NMR
spectra.]. See DOI: 10.1039/x0xx00000x
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Table 1 Selected results for screening the optimized reaction conditions a
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DOI: 10.1039/C6RA20732D
Entry
1
2
3
4
5
6
7
8
Catalyst
Cu(OAc)2
Cu(OAc)2·H2O
CuBr
Oxidant
Yield b (%)
TBHP
TBHP
TBHP
TBHP
TBHP
TBPB
H2O2
30
34
42
28
62
CuI
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
CuSO4·5H2O
48
Trace
Trace
-
92
90
m-CPBA
9
-
10c
11d
12e
TBHP
TBHP
TBHP
44
a
Reaction conditions: morpholine (1.5mmol), NCS (1.65mmol, 1.1equiv.), in 4mL
acetonitrile, stirring at room temperature for 3 h. To this reaction mixture were
added benzyl alcohol (1.8mmol, 1.2equiv.), catalyst (10 mol%) and oxidant
Scheme 2 Metal-catalyzed oxidative amidation of alcohols with amines
(7.5mmol, 5equiv.), stirring at 80°C for 24h. b Isolated yield. c Reaction performed
using 20 mol% of CuSO4·5H2O.
CuSO4·5H2O. Reaction performed using 20 mol% of CuSO4·5H2O and 3 equiv. of
TBHP.
d
Reaction performed using 50 mol% of
chloroamines, which were prepared from amines and without
purification, catalyzed by easily accessible copper salts under
base-free conditions (Scheme 2d).
e
At the beginning, morpholine 1a (1 equiv.) was treated with
N-chlorosuccinimide (NCS) (1.1 equiv.) in acetonitrile at room
temperature for 3h, and then benzyl alcohol 2a (1.2 equiv.),
Cu(OAc)2 (10 mol%) and TBHP (70 wt% in water, 5 equiv.) were
added to the reaction mixture under 80°C to generate the
amide product 3a in only 30% yield (Table 1, entry 1). In order
to improve the yield of the product, different parameters such
as catalyst, oxidant and stoichiometric mole ratio of reactants
were examined. Firstly, different catalysts were used instead
of Cu(OAc)2 to test the reaction and CuSO4·5H2O performed
best among these catalysts with a yield of 62% (Table 1,
entries 1-5). Then different oxidants were used to evaluate the
reaction. When we used TBPB as an oxidant, the yield of the
product was decreased apparently (Table 1, entry 6). And the
product obtained only in trace when we used H2O2 or m-CPBA
as oxidant (Table 1, entries 7-8). In the absence of an oxidant,
there was no product observed (Table 1, entry 9). When the
amount of catalyst increased to 20 mol%, the yield of product
was improved significantly (Table 1, entry 10). And it was
unnecessary to continue to increase the amount of catalyst
(Table 1, entry 11). The decrease in the amount of TBHP from
5 equiv. to 3 equiv. led to a collapse of the yield (Table 1, entry
12).
aliphatic alcohols, such as n-butanol and n-hexanol, were
employed as the substrate, the corresponding amide products
were obtained in moderate yield (Table 2, 3i-3l).
Table 2 Scope of alcohols a
With optimized reaction conditions in hand, a wide range of
commercial available alcohols was used to test the substrate
scope of this reaction. And the results were summarized in
Table 2. Aromatic alcohols with both electron-rich group, such
as CH3 (Table 2, 3b) and OMe (Table 2, 3c), and electron-
deficient group, such as NO2 (Table 2, 3d), Cl (Table 2, 3e) and
Br (Table 2, 3f), were well tolerated to provide the desired
amide products in good to excellent yields. Similarly,
heterocyclic alcohols 2g and 2h gave the corresponding amide
products in good yields (Table 2, 3g and 3h). Moreover, when
a
Reaction conditions: amine (1.5mmol), NCS (1.65mmol, 1.1 equiv.), in 4mL
acetonitrile, stirring at room temperature for 3 h. To this reaction mixture were
added alcohol (1.8mmol, 1.2 equiv.), CuSO4·5H2O (20 mol%) and TBHP (7.5mmol,
5 equiv.), stirring at 80°C for 24h.
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Next, an array of commercially available amines was used to
test the substrate scope of this reaction. And the results were
shown in Table 3. Disubstituted amines, such as cyclic (Table 3,
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3a, 3m-3o) and acyclic amines (Table 3, 3p-3t), showed great
activity to obtain the product in good yields. Furthermore,
monosubstituted amines were also showing excellent
tolerance (Table 3, 3u-3z), even when they were sterically
hindered (Table 3, 3w).
Table 3 Scope of amines a
Scheme 4 Proposed mechanism for amide synthesis
On the basis of previous studies, 7h, 16 a possible mechanism
was proposed as shown in Scheme 4. Firstly, alcohol is oxidized
to aldehyde by TBHP. And Cu (II) reacts with TBHP to form a
tert-butylperoxy radical, Cu (I) and H+ following the mechanism
proposed in literature.17 Then the tert-butylperoxy radical
captures hydrogen from aldehyde to generate an acyl radical,
as reported by Wan.14 And the protonated N-chloroamine is
then converted into an amino radical by a redox reaction as
well documented by Minisci.18 Finally, the acyl radical and the
amino radical couple to form the desired amide. To confirm
this hypothesis, the acyl radical, generated from benzyl alcohol
under our reaction conditions, was trapped with 2,2,6,6-
tetramethylpiperidine 1-oxyl (TEMPO), obtaining the TEMPO
adduct, , which was detected by HRMS (Scheme 5).
a
Reaction conditions: amine (1.5mmol), NCS (1.65mmol, 1.1 equiv.), in 4mL
acetonitrile, stirring at room temperature for 3 h. To this reaction mixture were
added benzyl alcohol (1.8mmol, 1.2 equiv.), CuSO4·5H2O (20 mol%) and TBHP
(7.5mmol, 5 equiv.), stirring at 80°C for 24h.
Scheme 5 Trapping of the acyl radical
In order to show the application of this new methodology,
the Cu-catalyzed one-pot oxidative amidation was used as a
key step to synthesis the biologically active N-
In conclusion, we have developed an efficient and green
one-pot procedure for the synthesis of amides via copper-
catalyzed direct oxidative amidation of aliphatic and aromatic
alcohols with N-chloroamines, prepared in situ from variously
substituted amines. This method integrates alcohol oxidation
and amide bond formation, which are usually accomplished
separately, into a single operation. And the use of copper as a
catalyst, TBHP as sole oxidant under mild reaction conditions
makes this methodology novel and environmentally benign.
More importantly, it has a wide substrate scope, and uses
cheap, abundant, and easily available reagents.
acetylprocainamide
5, which was an antiarrhythmic agent,
from commercial available 4-acetamidobenzyl alcohol
yield (Scheme 3).
4 in 68%
Scheme 3 Synthesis of N-acetylprocainamide
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16 Gaspa, S.; Porcheddu, A.; Luca, L. D. Org. BiVoimewoAlr.ticClehOenmlin.e,
Acknowledgements
2013, 11, 3803.
DOI: 10.1039/C6RA20732D
17 Minisci,F.; Fontana,F.; Araneo, S.; Recupero, F.; Banfi, S.;
Quici, S. J. Am. Chem. Soc. 1995, 117, 226.
18 F. Minisci, Synthesis, 1973, 1.
The research has been supported by the National Natural
Science Foundation of China (Grant No.21522604, U1463201
and 21402240); the youth in Jiangsu Province Natural Science
Fund (Grant No.BK20150031, BK20130913 and BY2014005-03);
a
Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions (PAPD).
Notes and references
1
2
3
Humphrey, J. M.; Chamberlin, A. R. Chem. Rev., 1997, 97
,
,
2243.
Montalbetti, C. A. G. N.; Falque, V. Tetrahedron, 2005, 61
10827.
Selected recent examples: (a) Kang, Y. J.; Chung, H. A.; Kim, J.
J.; Yoon, Y. J. Synthesis, 2002, 733; (b) Azumaya, I.; Okamoto,
T.; Imabeppu, F.; Takayanagi, H. Tetrahedron Lett., 2003, 59
2325; (c) Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org.
Lett., 2004, , 3477; (d) Shendage, D. M.; Froehlich, R.; Haufe,
G. Org. Lett., 2004, , 3675; (e) Black, D. A.; Arndtsen, B. A.
Org. Lett., 2006, , 1991; (f) Katritzky, A. R.; Cai C.; Singh, S. K.
,
6
6
8
J. Org. Chem., 2006, 71, 3375; (g) Roughley, S. D.; Jordan, A.
M. J. Med. Chem., 2011, 54, 3451.
(a) Yao, L.; Aubé, J. J. Am. Chem. Soc. 2007, 129, 2766; (b)
Schmidt, R. F. Ber. Dtsch. Chem. Ges.1924, 57, 704.
(a) Beckmann, E. Ber. Dtsch. Chem. Ges. 1886, 89, 988; (b)
Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007,
4
5
9
, 3599.
Ugi, I. Angew. Chem. 1962, 74, 9; Angew. Chem. Int. Ed. Engl.
1962, , 8.
6
7
1
Selected recent examples: (a) Yoo, W.-J.; Li, C.-J. J. Am. Chem.
Soc., 2006, 128, 13064; (b) Gao, J.; Wang, G.-U. J. Org. Chem.,
2008, 73, 2955; (c) Qian, C.; Zhang, X.; Li, J.; Xu, F.; Zhang, Y.;
Shen, Q. Organometallics, 2009, 28, 3856; (d) Li, J. M.; Xu, F.;
Zhang, Y.; Shen, Q. J. Org. Chem., 2009, 74, 2575; (e) Sarkar,
S. D.; Studer, A. Org. Lett., 2010,12,1992; (f) Ghosh, S. C.;
Ngiam, J. S. Y.; Chai, C. L. L.; Seayad, A. M.; Tuan, D. T.; Chen,
A. Adv. Synth. Catal., 2012, 354, 1407; (g) Subhash, C. G.;
Joyce, S. Y. N.; Seayad, A. M.; Dang T. T., Christina L. L. Chai,
and Anqi Chen. J. Org. Chem., 2012, 77, 8007; (h) Roberta, C.;
Andrea, P.; Giampaolo G.; Luca, L. D. Org. Lett., 2012, 14
5014.
,
8
9
Dobereiner, G. E.; Crabtree, R. H. Chem. Rev., 2010, 110, 681.
(a) Nordstrom, L. U.; Vogt, H.; Madsen, R. J. Am. Chem. Soc.,
2008, 130, 17672; (b) Watson, A. J. A.; Maxwell, A. C.;
Williams, J. M. J. Org. Lett., 2009, 11, 2667; (c) Zhang, Y.;
Chen, C.; Ghosh, S. C.; Li, Y.; Hong, S. H. Organometallics,
2010, 29, 1374; (d) Zweifel, T.; Naubron, J.-V.; Grützmacher,
H. Angew. Chem., Int. Ed., 2009, 48, 559.
10 (a) Shimizu, K.; Ohshima, K.; Satsuma, A. Chem.–Eur. J., 2009,
15, 9977; (b) Wang, Y.; Zhu, D.; Tang, L.; Wang S.; Wang, Z.
Angew. Chem., Int. Ed., 2011, 50, 8917; (c) Soulé, J.-F.;
Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc., 2011, 133
18550.
,
11 Wu, X.-F.; Sharif, M.; Pews-Davtyan, A.; Langer, P.; Ayub, K.;
Beller, M. Eur. J. Org. Chem. 2013, 2783.
12 Bantreil, X.; Fleith, C.; Martinez, J.; Lamaty, F. ChemCatChem
2012, 4, 1922.
13 Bantreil, X.; Kanfar, N.; Gehin, N.; Golliard, E.; Ohlmann, P.;
Martinez, J.; Lamaty, F. Tetrahedron, 2014, 70, 5093.
14 14. Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan, X. Angew.
Chem., Int. Ed. 2012, 51, 3231.
15 Xu, K.; Hu, Y.; Zhang, S.; Zha, Z.; Wang, Z. Chem.-Eur. J. 2012,
18, 9793.
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DOI: 10.1039/C6RA20732D
Copper-catalyzed one-pot oxidative amidation of both aliphatic and aromatic alcohols with
N-chloroamines, prepared in situ from many types of primary and secondary amines, to form
amides under mild conditions.