Copper-catalyzed aerobic oxidative synthesis of primary amides from (aryl)methanamines

Article abstract of DOI:10.1055/s-0031-1290302

A copper-catalyzed aerobic oxidative method for the synthesis of primary aryl amides has been developed, and the direct oxygenation of (aryl)methanamines to primary aryl amides by molecular oxygen showed convenient, practical, and environment-friendly advantages. This method will find wide application in chemistry and biology. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0031-1290302

LETTER
▌801
Letter
Copper-Catalyzed Aerobic Oxidative Synthesis of Primary Amides from
(Aryl)methanamines
Primary Amides from (Aryl)methanamines
Wei Xu,a Yuyang Jiang,b Hua Fu*a,b
a
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry, Tsinghua
University, Beijing 100084, P. R. of China
b
Key Laboratory of Chemical Biology (Guangdong Province), Graduate School of Shenzhen, Tsinghua University, Shenzhen 518057, P. R. of
China
Fax +86(10)62781695; E-Mail: fuhua@mail.tsinghua.edu.cn
Received: 08.12.2011; Accepted after revision: 08.01.2012
able progress in copper-catalyzed reactions with
inexpensive and low toxic copper catalysts, and wide ap-
plication with good functional tolerance has been investi-
gated.10,11 Recently, some copper-catalyzed aerobic
Abstract: A copper-catalyzed aerobic oxidative method for the
synthesis of primary aryl amides has been developed, and the direct
oxygenation of (aryl)methanamines to primary aryl amides by mo-
lecular oxygen showed convenient, practical, and environment-
friendly advantages. This method will find wide application in oxidative C–H functionalizations have been reported12,13
using O2 as the ideal oxidant.14 Herein, we report a conve-
chemistry and biology.
nient and efficient copper-catalyzed aerobic oxidative
synthesis of primary aryl amides from (aryl)methan-
amines.
Key words: copper, (aryl)methanamine, aryl amide, aerobic oxida-
tion, synthetic method
Phenylmethanamine (1a) was firstly used as the model
substrate to optimize the reaction conditions including
catalysts, bases, solvents, and reaction temperatures under
oxygen (1 bar). As shown in Table 1, four mixed solvents
were examined in the presence of 0.2 equivalents of CuBr
and two equivalents of K2CO3 (relative to amount of 1a)
at 140 °C (Table 1, entries 1–4), and DMSO–water pro-
vided 15% yield (Table 1, entry 2). Reaction yield reached
50% when the temperature was raised to 150 °C (Table 1,
entry 5). We tested other copper catalysts (Table 1, entries
6–10), and CuBr showed the best activity (Table 1, com-
pare entries 5, 6–10). The effects of bases were also inves-
tigated (Table 1, compare entries 5, 11–14), and K2CO3
afforded the highest yield (Table 1, entry 5). No target
product was observed in the absence of a base. We used
highly pure K2CO3 (99.997% purity) from Alfa Aesar as
the base in order to avoid the involvement of other metals
in the reaction,15 and a similar yield (49%) was provided
(Table 1, entry 15). The result showed no difference of re-
activity for this reaction by using analytic pure (99%) or
highly pure (99.997%) K2CO3 as the base. When air re-
placed oxygen as the oxidant, a low yield (13%) was af-
forded (Table 1, entry 16).
Aromatic compounds are ubiquitous in the world,1 and
their properties are highly depended on the functional
groups. Therefore, the functional-group transformation on
aromatic rings is a focusing field in chemistry. Aryl am-
ides are a very important class of compounds in chemistry
as well as biology,2 and they are widely used in the pro-
duction of pharmaceuticals, agricultural chemicals, and
fine chemicals.3 The traditional methods for the synthesis
of aryl amides include the reactions of activated carboxyl-
ic acid derivatives, such as acid chlorides, anhydrides, and
esters with ammonia,4 and the acid-catalyzed rearrange-
ments of ketoximes.5 Unfortunately, some waste chemical
byproducts, such as hydrogen chloride, carboxylic acids,
and alcohols, often appear together with these methods.
Hydrolysis of nitriles is also an usual method for the syn-
thesis of amides,6 but the previous preparation of nitriles
is needed. Oxidation of α-methylene groups in primary
amines is another approach to amides under mediation of
Ru oxidants.7 Tang and co-workers reported that the aer-
obic oxidation of amines with stoichiometric RuCl3 gave
nitriles as major products with the formation of small
amounts of amides.7a Kaneda and co-workers have devel-
oped the hydroxyapatite-bound Ru-complex-catalyzed
aerobic oxidation of various primary amines to nitriles
that were further hydrated to amides in the presence of
water.8 Mizuno et al. reported the oxygenation of amines
to primary amides by molecular oxygen from air in water
in the presence of supported ruthenium hydroxide cata-
lyst, Ru(OH)x/Al2O3.9 Recently, there has been remark-
We investigated the scope of copper-catalyzed aerobic
oxidative synthesis of primary aryl amides from (ar-
yl)methanamines under the optimized reaction conditions
{using 20 mol% of CuBr as the catalyst, 2 equiv of K2CO3
as the base [relative to amount of (aryl)methanamines],
and DMSO–H2O as the solvent under oxygen}.16 As
shown in Table 2, the corresponding primary aryl amides
were obtained in moderate to good yields for various ex-
amined substrates at 140–160 °C. The copper-catalyzed
aerobic oxidative method could tolerate various function-
al groups in the substrates including methyl (Table 2, en-
SYNLETT 2012, 23, 801–804
Advanced online publication: 27.02.2012
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9
3
6
-
5
2
1
4
1
4
3
7
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2
0
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DOI: 10.1055/s-0031-1290302; Art ID: ST-2011-W0757-L
© Georg Thieme Verlag Stuttgart · New York

802
W. Xu et al.
LETTER
give II. Further oxidation of II provides primary aryl
amide 2.
Table 1 Copper-Catalyzed Aerobic Oxidative Reaction of Phenyl-
methanamine (1a) to Benzamide (2a): Optimization of Reaction Con-
ditionsa
Table 2 Copper-Catalyzed Aerobic Oxidative Synthesis of Prima-
O
ry Aryl Amidesa
cat., base, solvent
NH2
NH2
O
H2O, temp, O2
CuBr, K2CO3, DMSO–H2O
Ar
NH2
Ar
NH2
1a
2a
O2, temp, time
1
2
Entry
Catalyst
Base
Solvent
Temp Yield
(°C)
(%)b
En- 1
try
Temp Time 2
(°C) (h)
Yield
(%)b
1
CuBr
CuBr
CuBr
CuBr
CuBr
CuCl2
Cu2O
Cu O
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
DMF–H2O
140 trace
140 15
O
2
DMSO–H2O
NH2
NH2
1
150 12
50
3
ethylene glycol–H2O 140 trace
4
DMA–H2O
140
0
1a
2a
5
DMSO–H2O
DMSO–H2O
DMSO–H2O
DMSO–H2O
DMSO–H2O
DMSO–H2O
150 50
150 39
150 12
150 trace
150 18
150 32
150 19
O
NH2
6
NH2
2
3
4
5
6
150 12
74
50
40
52
68
Me
7
Me
1b
2b
8
O
9
Cu(OAc)2 K2CO3
NH2
NH2
10
11
12
13
14
15
16
CuCl
CuBr
CuBr
CuBr
CuBr
CuBr
CuBr
K2CO3
150 10
MeO
MeO
1c
Cs2CO3 DMSO–H2O
2c
K3PO4
KOH
DMSO–H2O
DMSO–H2O
150
150
0
0
O
MeO
NH2
MeO
NH2
160
160
140
9
8
6
Na2CO3 DMSO–H2O
150 trace
150 49
1d
2d
K2CO3
K2CO3
DMSO–H2O
DMSO–H2O
O
13d
NH2
150
NH2
a Reaction conditions: phenylmethanamine (1a, 0.5 mmol), catalyst
(0.1 mmol), base (1 mmol), H2O (40 μL), solvent (2 mL) under oxy-
gen (1 bar), reaction time (12 h).
F
F
1e
2e
b Isolated yield.
O
c Using highly pure K2CO3 (99.997% purity) from Alfa Aesar compa-
ny as the base.
d Under air.
NH2
NH2
Cl
Cl
1f
2f
try 2), ether (Table 2, entries 3 and 4), C–F bond (Table 2,
entry 5), C–Cl bond (Table 2, entry 6), nitro (Table 2, en-
try 7), naphthalene ring (Table 2, entry 8), and N,O,S-het-
erocycles (Table 2, entries 9–12).
O
NH2
NH2
7
8
150 10
46
65
O2N
O2N
1g
We attempted the reaction of 4-methylbenzonitrile (3) un-
der the standard reaction conditions (using 20 mol% of
CuBr as the catalyst, 2 equiv of K2CO3 as the base, and
DMSO–H2O as the solvent under oxygen), and no reac-
tion was observed (Scheme 1). The result showed that no
nitrile intermediates formed during the synthesis of pri-
mary aryl amides from (aryl)methanamines. A possible
mechanism is suggested in Scheme 2. Copper-catalyzed
aerobic oxidation of (aryl)methanamine (1) first provides
the corresponding imine I, and then addition of I to water
2g
O
NH2
NH2
140 10
1h
2h
Synlett 2012, 23, 801–804
© Georg Thieme Verlag Stuttgart · New York

LETTER
Primary Amides from (Aryl)methanamines
803
Table 2 Copper-Catalyzed Aerobic Oxidative Synthesis of Prima-
starting materials, and economical and environmentally
friendly oxygen as the oxidant. The corresponding prima-
ry aryl amides were afforded in moderate to good yields.
The reactions could undergo sequential copper-catalyzed
aerobic oxidation of (aryl)methanamines to imines, addi-
tion of imines with water and further oxidation to provide
primary aryl amides. To the best of our knowledge, this
can be the first example to synthesize primary aryl amides
with copper catalysis, so this method will find wide appli-
cation in organic and medicinal chemistry.
ry Aryl Amidesa (continued)
O
CuBr, K2CO3, DMSO–H2O
Ar
NH2
Ar
NH2
O2, temp, time
1
2
En- 1
try
Temp Time 2
(°C) (h)
Yield
(%)b
90
O
NH2
NH2
9
140
6
N
Acknowledgment
N
1i
The authors wish to thank the National Natural Science Foundation
of China (Grant Nos. 20972083 and 21172128), and the Ministry of
Science and Technology of China (Grant No. 2012CB722600) for
financial support.
2i
O
NH2
NH2
N
10
11
12
140
140
140
5
8
7
80
76
81
N
1j
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.onmornifaItngoniSmuortinfaopnrtIgiSutpor
2j
O
O
NH2
O
NH2
References
1k
(1) Hassan, J.; Sevignon, M.; Gozzi, C.; Schulz, E.; Lemaire, M.
Chem. Rev. 2002, 102, 1359.
(2) Humphrey, J. M.; Chamberlin, A. R. Chem. Rev. 1997, 97,
2243.
(3) (a) Mabermann, C. E. In Encyclopedia of Chemical
Technology, Vol. 1; Kroschwitz, J. I., Ed.; Wiley: New
York, 1991, 251–266. (b) Lipp, D. In Encyclopedia of
Chemical Technology, Vol. 1; Kroschwitz, J. I., Ed.; Wiley:
New York, 1991, 266–287. (c) Opsahl, R. In Encyclopedia
of Chemical Technology, Vol. 2; Kroschwitz, J. I., Ed.;
Wiley: New York, 1991, 346–356. (d) Larock, R. C.
Comprehensive Organic Transformations, 2nd ed.; Wiley-
VCH: New York, 1999.
2k
O
S
NH2
S
NH2
1l
2l
a Reaction conditions: arylmethanamine (1, 0.5 mmol), CuBr (0.1
mmol), K2CO3 (1 mmol), DMSO (2 mL), H2O (40 μL) under oxygen
(1 atm).
b Isolated yield.
(4) (a) Smith, M. B.; March, J. March’s Advanced Organic
Chemistry, 5th ed.; Wiley: New York, 2001. (b) Smith, M.
B. Organic Synthesis, 2nd ed.; McGraw-Hill: New York,
2002.
(5) (a) Fujiwara, H.; Ogasawara, Y.; Yamaguchi, K.; Mizuno,
N. Angew. Chem. Int. Ed. 2007, 46, 5202. (b) Alia, M. A.;
Punniyamurthya, T. Adv. Synth. Catal. 2010, 352, 288.
(c) Ramón, R. S.; Bosson, J.; Díez-González, S.; Marion, N.;
Nolan, S. P. J. Org. Chem. 2010, 75, 1197. (d) Owston, N.
A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9, 3599.
(e) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.
2007, 9, 73.
(6) (a) Goto, A.; Endo, K.; Saito, S. Angew. Chem. Int. Ed.
2008, 47, 3607. (b) Yamaguchi, K.; Matsushita, M.;
Mizuno, N. Angew. Chem. Int. Ed. 2004, 43, 1576. (c) Kim,
A. Y.; Bae, H. S.; Park, S.; Park, S.; Park, K. H. Catal. Lett.
2011, 141, 685. (d) Mitsudome, T.; Mikami, Y.; Mori, H.;
Arita, S.; Mizugaki, T.; Jitsukawa, K.; Kaneda, K. Chem.
Commun. 2009, 3258. (e) Cadierno, V.; Díez, J.; Francos, J.;
Gimeno, J. Chem. Eur. J. 2010, 16, 9808. (f) Cadierno, V.;
Francos, J.; Gimeno, J. Chem. Eur. J. 2008, 14, 6601. (g) He,
J.; Yamaguchi, K.; Mizuno, N. J. Org. Chem. 2011, 76,
4606.
O
CN
CuBr, K2CO3, DMSO–H2O
NH2
O2, 150 °C, 12 h
Me
Me
no reaction
3
2b
Scheme 1 Copper-catalyzed treatment of 4-methylbenzonitrile (3)
under the standard reaction conditions
OH
H2O
CuBr, K2CO3, O2
oxidation
Ar
Ar
NH2
NH
Ar
NH2
1
I
II
O
CuBr, K2CO3, H2O, O2
Ar
NH2
2
Scheme 2 Possible mechanism for the synthesis of primary aryl
amides
(7) (a) Tang, R.; Diamond, S. E.; Neary, N.; Mares, F. J. Chem.
Soc., Chem. Commun. 1978, 562. (b) Tanaka, K.; Yoshifuji,
S.; Nitta, Y. Chem. Pharm. Bull. 1988, 36, 3125.
(8) Mori, K.; Yamaguchi, K.; Mizugaki, T.; Ebitani, K.;
Kaneda, K. Chem. Commun. 2001, 461.
In summary, we have developed a simple and practical
copper-catalyzed domino method for the synthesis of pri-
mary aryl amides. The protocol uses cheap and readily
available CuBr as the catalyst, (aryl)methanamines as the
© Georg Thieme Verlag Stuttgart · New York
Synlett 2012, 23, 801–804

804
W. Xu et al.
LETTER
(9) Kim, J. W.; Yamaguchi, K.; Mizuno, N. Angew. Chem. Int.
Ed. 2008, 47, 9249.
N.; Ali, M. A.; Paul, R.; Punniyamurthy, T. J. Org. Chem.
2009, 74, 8719. (d) Wang, H.; Wang, Y.; Liang, D.; Liu, L.;
Zhang, J.; Zhu, Q. Angew. Chem. Int. Ed. 2011, 50, 5677.
(e) Lu, J.; Jin, Y.; Liu, H.; Jiang, Y.; Fu, H. Org. Lett. 2011,
13, 3694.
(10) For recent reviews on copper-catalyzed cross-couplings,
see: (a) Ley, S. V.; Thomas, A. W. Angew. Chem. Int. Ed.
2003, 42, 5400. (b) Kunz, K.; Scholz, U.; Ganzer, D. Synlett
2003, 2428. (c) Beletskaya, I. P.; Cheprakov, A. V. Coord.
Chem. Rev. 2004, 248, 2337. (d) Evano, G.; Blanchard, N.;
Toumi, M. Chem. Rev. 2008, 108, 3054. (e) Ma, D.; Cai, Q.
Acc. Chem. Res. 2008, 41, 1450. (f) Monnier, F.; Taillefer,
M. Angew. Chem. Int. Ed. 2009, 48, 6954. (g) Rao, H.; Fu,
H. Synlett 2011, 745; and references cited therein.
(14) For some reviews, see: (a) Stahl, S. S. Angew. Chem. Int. Ed.
2004, 43, 3400. (b) Punniyamurthy, T.; Velusamy, S.; Iqbal,
J. Chem. Rev. 2005, 105, 2329. (c) Wendlandt, A. E.; Suess,
A. M.; Stahl, S. S. Angew. Chem. Int. Ed. 2011, 50, 11062.
(d) Wang, J.-R.; Fu, Y.; Zhang, B.-B.; Cui, X.; Liu, L.; Guo,
Q.-X. Tetrahedron Lett. 2006, 47, 8293.
(11) For selected papers, see: (a) Klapars, A.; Antilla, J. C.;
Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2001, 123,
7727. (b) Klapars, A.; Huang, X. H.; Buchwald, S. L. J. Am.
Chem. Soc. 2002, 124, 7421. (c) Antilla, J. C.; Klapars, A.;
Buchwald, S. L. J. Am. Chem. Soc. 2002, 124, 11684.
(d) Okano, K.; Tokuyama, H.; Fukuyama, T. Org. Lett.
2003, 5, 4987. (e) Gujadhur, R. K.; Bates, C. G.;
(15) K2CO3 (99.997%), Mg (2 ppm), Na (8 ppm), other elements
including Al, Sb, As, Ba, Bi, B, Cd, Ca, Cr, Co, Cu, In, Fe,
Pb, Li, Mn, Mo, Ni, P, Si, Te, Sn, Ti, V, Zn, Zr (sought but
not detected). The data were provided by Alfa Aesar.
(16) General Procedure for the Synthesis of Compounds 2a–l
A 25 mL Schlenk tube was charged with a magnetic stirrer,
(aryl)methanamine (1, 0.5 mmol), K2CO3 (1 mmol, 138 mg),
and CuBr (0.1 mmol, 14 mg) in mixed solvent of DMSO (2
mL) and H2O (40 μL). The mixture was allowed to stir under
O2 (1 atm) at 140–160 °C for 6–12 h (see Table 2 for details).
After completion of the reaction, the resulting solution was
cooled to r.t. and filtered, and the solvent of filtrate was
removed with the aid of a rotary evaporator. The residue was
purified by column chromatography on silica gel using PE–
EtOAc as eluent to provide the desired product 2.
Analytical Data for Two Typical Examples 3-
Venkataraman, D. Org. Lett. 2001, 3, 4315. (f) Gajare, A. S.;
Toyota, K.; Yoshifuji, M.; Yoshifuji, F. Chem. Commun.
2004, 1994. (g) Ma, D.; Zhang, Y.; Yao, J.; Wu, S.; Tao, F.
J. Am. Chem. Soc. 1998, 120, 12459. (h) Ma, D.; Cai, Q.;
Zhang, H. Org. Lett. 2003, 5, 2453. (i) Zhu, L.; Cheng, L.;
Zhang, Y.; Xie, R.; You, J. J. Org. Chem. 2007, 72, 2737.
(12) (a) Chen, X.; Hao, X.-S.; Goodhue, C. E.; Yu, J.-Q. J. Am.
Chem. Soc. 2006, 128, 6790. (b) King, A. E.; Huffman, L.
M.; Casitas, A.; Costas, M.; Ribas, X.; Stahl, S. S. J. Am.
Chem. Soc. 2010, 132, 12068. (c) Armstrong, A.; Collins, J.
C. Angew. Chem. Int. Ed. 2010, 49, 2282. (d) Zhou, W.;
Zhang, L.; Jiao, N. Angew. Chem. Int. Ed. 2009, 48, 7094.
(e) Monguchi, D.; Fujiwara, T.; Furukawa, H.; Mori, A.
Org. Lett. 2009, 11, 1607. (f) Wang, Q.; Schreiber, S. L.
Org. Lett. 2009, 11, 5178. (g) Kawano, T.; Hirano, K.;
Satoh, T.; Miura, M. J. Am. Chem. Soc. 2010, 132, 6900.
(h) John, A.; Nicholas, K. M. J. Org. Chem. 2011, 76, 4158.
(i) Matsuda, N.; Hirano, K.; Satoh, T.; Miura, M. Org. Lett.
2011, 13, 2860. (j) Miyasaka, M.; Hirano, K.; Satoh, T.;
Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13,
359. (k) Guo, S.; Qian, B.; Xie, Y.; Xia, C.; Huang, H. Org.
Lett. 2011, 13, 522.
Pyridinecarboxamide (2i)17 Eluent: EtOAc; yield 55 mg
(90%); white solid; mp 131–132 °C (lit.17 131–132 °C). 1H
NMR (300 MHz, DMSO-d6): δ = 9.09 (s, 1 H), 8.74 (d, 1 H,
J = 4.1 Hz), 8.26 (d, 2 H, J = 8.3 Hz), 7.68 (s, 1 H), 7.53 (dd,
1 H, J = 4.8, 4.8 Hz). 13C NMR (75 MHz, DMSO-d6):
δ = 166.5, 151.9, 148.7, 135.3, 129.7, 123.5. ESI-MS:
m/z = 123.4 [M + H]+.
2-Furancarboxamide (2k)17 Eluent: PE–EtOAc (1:1); yield
42 mg (76%); white solid; mp 140–142 °C (lit.17 140–142
°C). 1H NMR (300 MHz, DMSO-d6): δ = 7.81 (s, 1 H), 7.76
(s, 1 H), 7.37 (s, 1 H), 7.10 (d, 1 H, J = 3.4 Hz), 6.60 (dd, 1
H, J = 1.7, 1.7 Hz). 13C NMR (75 MHz, DMSO-d6): δ =
159.4, 148.0, 145.0, 113.6, 111.8. ESI-MS: m/z = 112.5
[M + H]+.
(13) (a) Brasche, G.; Buchwald, S. L. Angew. Chem. Int. Ed.
2008, 47, 1932. (b) Ueda, S.; Nagasawa, H. Angew. Chem.
Int. Ed. 2008, 47, 6411. (c) Saha, P.; Ramana, T.; Purkait,
(17) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett.
2007, 9, 73.
Synlett 2012, 23, 801–804
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