Direct oxidative amidation of aldehydes with anilines under mechanical milling conditions

Article abstract of DOI:10.1021/jo800075t

(Chemical Equation Presented) Oxone is found to be an effective oxidant for the oxidative amidation of aldehydes with anilines to furnish amides in a one-pot process under mechanical milling conditions.

Full text of DOI:10.1021/jo800075t

achieved by the direct oxidation of alcohols and amines.12
However, most of these systems involved toxic solvents and
transition-metal catalysts. Thus, developing new procedures for
the synthesis of amides in both economic and eco-friendly ways
is highly desirable. Recently, Wolf and co-worker presented an
elegant alternative approach to amides without metal catalyst.13
Solvent-free organic reactions have drawn the attention of
the chemical community for many years due to the public’s
increasing concern about environmentally benign processes. Our
contribution to solvent-free reactions was focused on those
promoted by the ball-milling technique.14 In light of our recent
success in this field,15 we are interested in the direct oxidative
amidations of aldehydes with amines under mechanical milling
conditions.
Direct Oxidative Amidation of Aldehydes with
Anilines under Mechanical Milling Conditions
Jie Gao and Guan-Wu Wang*
Hefei National Laboratory for Physical Sciences at Microscale,
Joint Laboratory of Green Synthetic Chemistry, and Department
of Chemistry, UniVersity of Science and Technology of China,
Hefei, Anhui, 230026, P. R. China
gwang@ustc.edu.cn
ReceiVed January 12, 2008
Oxone (potassium peroxymonosulfate, 2KHSO5·KHSO4·K2-
SO4), an efficient oxidant, found its broad applications in organic
synthesis recently due to its versatility, stability, the simple
handling, the nontoxic nature, and low costs.16 Because of its
prominent properties, we were intrigued to explore the feasibility
of Oxone-promoted oxidative amidation. Herein, we report an
efficient oxidative amidation process with Oxone under me-
chanical milling conditions (eq 1).
Oxone is found to be an effective oxidant for the oxidative
amidation of aldehydes with anilines to furnish amides in a
one-pot process under mechanical milling conditions.
The amide functional group is of importance in view of
synthetic and biological aspects. Traditional synthetic methods
for amides are mostly based on activated acid derivatives and
amines. However, there are some limitations, including the
lability of activated carboxylic acid derivatives and tedious
procedures.
In our initial study, we chose the reaction of 3-nitrobenzal-
dehyde with p-toluidine and Oxone as the model reaction.
Typically, a mixture of 3-nitrobenzaldehyde (0.1 mmol), p-
toluidine (0.1 mmol), and Oxone (0.2 mmol) was milled
vigorously at a rate of 1800 revolutions per minute (30 Hz) at
room temperature for 90 min.15b After usual workup, the
To circumvent these problems, alternative strategies toward
the synthesis of amides have been explored for years. Due to
the advanced properties, the use of transition-metal catalysts
has developed rapidly in organic synthesis, and was also
employed to promote the formation of amides. For example,
transition-metal catalyzed amidations of nitriles,1 aldehydes,2
aldoximes,3 alcohols,4 alkenes,5 alkynes,6 and haloarenes7 with
amines have been reported. Although significant achievements
were made, the relatively expensive transition metals greatly
restricted the application of this methodology. Another notable
access to the amide moiety was through the reactions of organic
azides with terminal alkynes,8 or thio acids,9 which exhibited
new promising routes for amide synthesis. Recently, the
oxidative transformation of aldehydes10 or arylalkynes11 to
amides has received much attention. Gunanathan et al. reported
a successful example, in which the formation of amides was
(8) Cho, S. H.; Yoo, E. J.; Bae, I.; Chang, S. J. Am. Chem. Soc. 2005,
127, 16046.
(9) (a) Park, S.-D.; Oh, J.-H.; Lim, D. Tetrahedron Lett. 2002, 43, 6309.
(b) Shangguan, N.; Katukojvala, S.; Greenberg, R.; Williams, L. J. J. Am.
Chem. Soc. 2003, 125, 7754. (c) Merkx, R.; Brouwer, A. J.; Rijkers, D. T.
S.; Liskamp, M. J. Org. Lett. 2005, 7, 1125.
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Li, C.-J. J. Am. Chem. Soc. 2006, 128, 13064.
(11) Chan, W.-K.; Ho, C.-M.; Wong, M.-K.; Che, C.-M. J. Am. Chem.
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(13) Ekoue-Kovi, K.; Wolf, C. Org. Lett. 2007, 9, 3429.
(14) For a review, see: (a) Rodr´ıguez, B.; Bruckmann, A.; Rantanen,
T.; Bolm, C. AdV. Synth. Catal. 2007, 349, 2213. For examples, see: (b)
Balema, V. P.; Wiench, J. W.; Pruski, M.; Pecharsky, V. K. J. Am. Chem.
Soc. 2002, 124, 6244. (c) Rodr´ıguez, B.; Rantanen, T.; Bolm, C. Angew.
Chem. Int. Ed. 2006, 45, 6924.
(15) For a review, see: Wang, G.-W. Fullerene Mechanochemistry. In
Encyclopedia of Nanoscience and Nanotechnology; Nalwa, H. S., Ed.;
American Scientific Publishers: Stevenson Ranch, 2004; Vol. 3, p 557.
For mechanochemical nonfullerene reactions, see: (a) Zhang, Z.; Dong,
Y.-W.; Wang, Y.-W.; Komatsu, K. Synlett 2004, 61. (b) Zhang, Z.; Wang,
G.-W.; Miao, C.-B.; Dong, Y.-W.; Shen, Y.-B. Chem. Commun. 2004, 1832.
(c) Zhang, Z.; Gao, J.; Xia, J.-J. Org. Biomol. Chem. 2005, 3, 1617. (d)
Wang, G.-W.; Wu, X.-L. AdV. Synth. Catal. 2007, 349, 1977. (e) Wu, X.-
L.; Xia, J.-J.; Wang, G.-W. Org. Biomol. Chem. 2008, 6, 548.
(16) (a) Yang, D.; Zhang, C. J. Org. Chem. 2000, 66, 4814. (b) Bolm,
C.; Magnus, A. S.; Hildebrand, J. P. Org. Lett. 2000, 2, 1173. (c) Travis,
B. R.; Sivakumar, M.; Hollist, G. O.; Borhan, B. Org. Lett. 2003, 5, 1031.
(d) Plietker, B. Org. Lett. 2004, 6, 289. (e) Singh, R.; Kissling, R. M.;
Letellier, M.-A.; Nolan, S. P. J. Org. Chem. 2004, 69, 209. (f) Ge, H.-Q.
Synlett 2004, 11, 2046.
(1) (a) Murahashi, S.-I.; Naota, T.; Saito, E. J. Am. Chem. Soc. 1986,
108, 7846. (b) Cobley, C. J.; van den Heuvel, M.; Abbadi, A.; de Vries, J.
G. Tetrahedron Lett. 2000, 41, 2467.
(2) Tillack, A.; Rudloff, I.; Beller, M. Eur. J. Org. Chem. 2001, 523.
(3) Park, S.; Choi, Y.; Han, H.; Yang, S. H.; Chang, S. Chem. Commun.
2003, 1936.
(4) Owston, N. A.; Parker, A. J.; Williams, J. M. J. Org. Lett. 2007, 9,
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Knapton, D. J.; Meyer, T. Y. Org. Lett. 2004, 6, 687. (c) Uenoyama, Y.;
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10.1021/jo800075t CCC: $40.75 © 2008 American Chemical Society
Published on Web 03/11/2008
J. Org. Chem. 2008, 73, 2955-2958
2955

TABLE 1. Oxidative Amidation of 3-Nitrobenzaldehyde with
TABLE 2. Direct Oxidative Amidation of Aldehydes with Anilines
Using Oxone as the Oxidant under Solvent-Free Conditionsa
p-Toluidine under Various Conditionsa
entry
oxidant
additives
4Å MS
MgSO4
MgSO4
solvent
yieldb (%)
1
2
3
4
5
Oxone
Oxone
Oxone
Oxone
Oxone
I2
61
68
75
11
trace
0
CH3CNc
toluenec
MgSO4
MgSO4
6
7
8
9
10
11
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
MgSO4/ZnCl2
MgSO4/CuCl
MgSO4/CuBr
MgSO4/TsOH
MgSO4/KHSO4
0
trace
0
0
0
a Aldehyde (1.0 equiv), aniline (1.0 equiv), MgSO4 (1.0 equiv), Oxone
(2.0 equiv) in MM200 ball-mill. b Isolated yields obtained by chromatog-
raphy on silica gel.
a 3-Nitrobenzaldehyde (1.0 equiv), p-toluidine (1.0 equiv), MgSO4 (1.0
equiv), and Oxone (2.0 equiv) in MM200 ball-mill. b Isolated yields. c 3-
Nitrobenzaldehyde (1.0 equiv), p-toluidine (1.0 equiv), MgSO4 (1.0 equiv),
and Oxone (2.0 equiv) in solvent.
SCHEME 1. Possible Pathway for the Direct Oxidative
Amidation of Aldehydes with Anilines
obtained product turned out to be the corresponding amide 3a,
i.e., 3-nitro-N-p-tolylbenzamide, yet in moderate yield of 61%
along with various unidentified byproducts (entry 1, Table 1).
We envisioned that the reaction might proceed through an imine
intermediate; the thus generated water was harmful to the
reaction. Molecular sieves (4 Å) were therefore added to remove
the formed water. As desired, the product yield was improved
slightly (entry 2, Table 1). Anhydrous magnesium sulfate was
then examined. Much to our delight, the amidation reaction
occurred more efficiently and cleanly to afford the product in
75% yield (entry 3, Table 1). When the imine generated from
3-nitrobenzaldehyde with p-toluidine was utilized as the
starting substrate to react with Oxone, the same amide 3a was
obtained in 77% yield, which was slightly higher than the one-
pot process.
To demonstrate the advantages of our solvent-free process,
we further studied the oxidative amidation in organic solvents,
including acetonitrile and toluene. As a result, the corresponding
amide was obtained in rather low yields (entries 4 and 5, Table
1). Other oxidants including K2S2O8 and I2, were also examined.
However, no reaction was observed (entries 6-11, Table 1).
Oxone proved to be the most effective oxidant for this reaction.
When the oxidant loading was reduced to 1.0 equiv, the yield
decreased significantly. Hence 2.0 equiv of Oxone were
necessary for this reaction.
With the optimized conditions in hand, we next investigated
the scope and generality of this transformation with various
aromatic aldehydes and anilines. The results are shown in Table
2. Although aryl aldehydes were prone to be oxidized to acids,
only trace acids were observed in our procedure, which revealed
that Oxone reacted chemoselectively with the imines rather than
the aldehydes.
Anilines substituted with either electron-donating or electron-
withdrawing groups, including p-toluidine, p-bromoaniline,
and p-chloroaniline, exhibited similar activities (entries 1-11,
Table 2). When aldehydes bearing electron-withdrawing groups
were examined, the corresponding amides were obtained in
moderate to good yields (entries 1-10, Table 2). The steric
hindrance of the substituted groups on the phenyl rings of
aldehydes was deleterious to the reaction, leading to decreased
yields. For example, 2-nitrobenzaldehyde afforded the desired
amides in remarkably decreased yields (entries 4 and 9 vs entries
1 and 5, Table 2). A heterocyclic aldehyde, namely 2-thiophen-
ecarboxaldehyde, was also investigated. Under the same condi-
tions, the desired product, N-(4-methylphenyl)thiophene-2-
carboxamide, was obtained in 42% yield (entry 11, Table 2).
Extending our procedure to aryl aldehydes with electron-
donating groups and aliphatic aldehydes was unworkable,
probably due to the electronic factors. These results indicated
that the reaction was sensitive to the electronic character of
aldehydes.
It is noteworthy that replacing the aldehydes with corre-
sponding carboxylic acids did not afford the desired amides.
Therefore, the possibility of oxidation of aldehydes to carboxylic
acids by Oxone, followed by reaction with anilines to give
amides should be excluded. Although the exact process of this
transformation is unclear at the present stage, we still attempted
to propose a tentative mechanism for the amidation reaction of
aldehydes with anilines based on the above results and the
known examples (Scheme 1). We envisioned that this direct
oxidative amidation reaction may proceed by two pathways. In
pathway A, imines were formed from aldehydes and anilines
rapidly, which were oxidized by Oxone to generate oxaziridines
4 as the key intermediates. Rearrangement of oxaziridines to
amides is known for both photochemical and thermal reactions.17
The initial cleavage of the N-O bond followed by migration
of the substituent (hydrogen) trans to the nitrogen lone pair
results in the formation of amides 3. In pathway B, carbinola-
mine intermediates 5 were generated after the nucleophilic
2956 J. Org. Chem., Vol. 73, No. 7, 2008

d6, 75 MHz) δ 163.9, 139.0, 136.2, 133.1, 132.4, 129.1, 128.5,
120.5, 118.3, 113.8, 20.5; HRMS calcd for C15H12N2O m/z
236.0950, found m/z 236.0954.
addition of anilines to aldehydes, and then were oxidized
by Oxone to form the desired amide products. Even though
control experiments showed that imines could be employed as
the starting substrates to perform the amidation reaction to
generate the amide products directly, the exact mechanism of
this reaction remains obscure and both pathways could be
operational.
In conclusion, we have demonstrated a simple and novel one-
pot protocol to oxidize aryl aldehydes and anilines directly to
amides in synthetic useful yields under mechanical milling
conditions for the first time. Compared with the traditional
liquid-phase reaction, this novel solvent-free and metal catalyst-
free procedure makes the synthesis of amides more efficient,
low cost, and ecofriendly. To the best of our knowledge, this is
unprecedented. Further investigations in this direction are in
progress.
2-Nitro-N-p-tolylbenzamide (3d): mp 146-147 °C (lit.18 mp
146-148 °C); IR (KBr) cm-1 3275, 1649, 1598, 1526, 1405, 1355,
1323, 1265, 908, 812, 786, 708, 511; 1H NMR (CDCl3, 300 MHz)
δ 8.10 (d, J ) 8.0 Hz, 1 H), 7.74-7.69 (m, 1 H), 7.64-7.58 (m,
2 H), 7.50 (bs, 1 H), 7.46 (d, J ) 8.1 Hz, 2 H), 7.17 (d, J ) 8.1
Hz, 2 H), 2.35 (s, 3 H); 13C NMR (CDCl3, 75 MHz) δ 164.6, 146.3,
134.9, 134.8, 133.9, 132.9, 130.6, 129.6, 128.7, 124.6, 120.8,
21.0; HRMS calcd for C14H12N2O3 m/z 256.0848, found m/z
256.0843.
N-(4-Bromophenyl)-3-nitrobenzamide (3e): mp 179-180 °C;
1H NMR (DMSO-d6, 300 MHz) δ 10.69 (s, 1 H), 8.78 (s, 1 H),
8.45 (d, J ) 8.4 Hz, 1 H), 8.40 (d, J ) 7.5 Hz, 1 H), 7.85 (t, J )
8.0 Hz, 1 H), 7.77 (d, J ) 8.6 Hz, 2 H), 7.58 (d, J ) 8.6 Hz, 2 H).
This is a known compound, and the spectral data are identical to
those reported in the literature.21
N-(4-Bromophenyl)-4-nitrobenzamide (3f): mp 238-240 °C
(lit.22 mp 240 °C); H NMR (DMSO-d6, 300 MHz) δ 10.67 (s,
1
Experimental Section
1H), 8.38 (d, J ) 8.7 Hz, 2 H), 8.18 (d, J ) 8.7 Hz, 2 H), 7.77 (d,
J ) 8.8 Hz, 2 H), 7.57 (d, J ) 8.8 Hz, 2 H). This is a known
compound, and the spectral data are identical to those reported in
the literature.23
General Procedure for the Oxidative Amidation of Aldehydes
and Anilines Leading to Amides. A mixture of aryl aldehyde (1.0
equiv), aniline (1.0 equiv), MgSO4 (1.0 equiv), and Oxone (2.0
equiv) was introduced, together with a stainless ball of 7.0 mm
diameter, into a stainless steel jar (5 mL). The same mixture was
also introduced into a second parallel jar. The two reaction vessels
were closed and fixed on the vibration arms of a ball-milling
apparatus (Retsch MM200 mixer mill, Retsch GmbH, Haan,
Germany) and were vibrated vigorously at a rate of 1800 revolutions
per minute (30 Hz) at room temperature for 90 min. After
completion of reaction, the reaction mixture was collected and
dissolved in ethyl acetate. The solution was then evaporated to
dryness and the resulting solid was purified by column chroma-
tography on silica gel using ethyl acetate/petroleum ether as the
eluent.
N-(4-Bromophenyl)-4-cyanobenzamide (3g): mp 205-206 °C;
IR (KBr) cm-1 3354, 2225, 1674, 1591, 1524, 1488, 1393, 1312,
1290, 1239, 1068, 1004, 858, 829, 762, 655, 507; 1H NMR (DMSO-
d6, 300 MHz) δ 10.59 (s, 1 H), 8.10 (d, J ) 8.1 Hz, 2 H), 8.03 (d,
J ) 8.1 Hz, 2 H), 7.76 (d, J ) 8.7 Hz, 2 H), 7.56 (d, J ) 8.7 Hz,
2 H); 13C NMR (DMSO-d6, 75 MHz) δ 164.3, 138.7, 138.1, 132.5,
131.5, 128.6, 122.4, 118.3, 115.9, 114.0; HRMS calcd for
C14H9N2O79Br m/z 299.9898, found m/z 299.9900.
N-(4-Bromophenyl)-3,4-dichlorobenzamide (3h): mp 158-160
°C; IR (KBr) cm-1 3303, 1652, 1591, 1522, 1490, 1393, 1312,
1240, 1137, 1073, 1032, 1011, 822, 768, 668, 503; 1H NMR
(DMSO-d6, 300 MHz) δ 10.49 (s, 1 H), 8.21 (s, 1 H), 7.94 (d, J )
8.5 Hz, 1 H), 7.82 (d, J ) 8.5 Hz, 1 H), 7.75 (d, J ) 8.7 Hz, 2 H),
7.56 (d, J ) 8.7 Hz, 2 H); 13C NMR (CDCl3, 75 MHz) δ 163.9,
136.7, 136.6, 134.4, 133.4, 132.2, 130.9, 129.4, 126.4, 122.3, 118.0;
HRMS calcd for C13H8NO35Cl279Br m/z 342.9166, found m/z
342.9159.
3-Nitro-N-p-tolyl-benzamide (3a): mp 158-159 °C (lit.18 mp
159-161 °C); IR (KBr) cm-1 3300, 1647, 1597, 1526, 1405, 1347,
1326, 1266, 814, 710, 514; 1H NMR (CDCl3, 300 MHz) δ 8.68 (s,
1 H), 8.39 (d, J ) 8.1 Hz, 1 H), 8.25 (d, J ) 7.5 Hz, 1 H), 7.92
(bs, 1 H), 7.69 (t, J ) 8.0 Hz, 1 H), 7.52 (d, J ) 8.1 Hz, 2 H), 7.19
(d, J ) 8.1 Hz, 2 H), 2.35 (s, 3 H); 13C NMR (DMSO-d6, 75 MHz)
δ 163.0, 147.8, 136.3, 136.1, 134.1, 133.2, 130.1, 129.1, 126.0,
122.4, 120.5, 20.5; HRMS calcd for C14H12N2O3 m/z 256.0848,
found m/z 256.0850.
N-(4-Bromophenyl)-2-nitrobenzamide (3i): mp 200-202 °C;
IR (KBr) cm-1 3284, 1652, 1592, 1522, 1489, 1392, 1353,
1
1312, 1068, 1009, 820, 709, 505; H NMR (CDCl3, 300 MHz) δ
8.13 (d, J ) 8.0 Hz, 1 H), 7.74 (t, J ) 7.4 Hz, 1 H), 7.67-7.62
(m, 2 H), 7.48 (s, 4 H); 13C NMR (DMSO-d6, 75 MHz) δ 164.2,
146.4, 138.2, 134.1, 132.4, 131.6, 131.0, 129.2, 128.9, 124.2, 121.6,
115.6; HRMS calcd for C13H9N2O379Br m/z 319.9797, found m/z
319.9795.
4-Nitro-N-p-tolylbenzamide (3b): mp 201-203 °C (lit.19 mp
1
203.5-204 °C); H NMR (CDCl3, 300 MHz) δ 8.32 (d, J ) 8.1
Hz, 2 H), 8.03 (d, J ) 8.1 Hz, 2 H), 7.84 (bs, 1 H), 7.51 (d, J )
8.1 Hz, 2 H), 7.20 (d, J ) 8.1 Hz, 2 H), 2.36 (s, 3 H). This is a
known compound, and the spectral data are identical to those
reported in the literature.20
N-(4-Chlorophenyl)-3-nitrobenzamide (3j): mp 174-176 °C;
IR (KBr) cm-1 3303, 1656, 1596, 1525, 1494, 1400, 1348,
1323, 1091, 826, 717, 514; 1H NMR (CDCl3, 300 MHz) δ 8.69 (s,
1 H), 8.42 (d, J ) 8.0 Hz, 1 H), 8.26 (d, J ) 7.5 Hz, 1 H), 7.94
(s, 1 H), 7.72 (t, J ) 8.0 Hz, 1 H), 7.62 (d, J ) 8.6 Hz, 2 H), 7.37
(d, J ) 8.6 Hz, 2 H); 13C NMR (DMSO-d6, 75 MHz) δ 163.3,
147.7, 137.6, 136.0, 134.1, 130.1, 128.5, 127.8, 126.2, 122.4,
122.0; HRMS calcd for C13H9N2O335Cl m/z 276.0302, found m/z
276.0303.
N-(4-Methylphenyl)thiophene-2-carboxamide (3k): mp 162-
164 °C (lit.24 mp 163 °C); 1H NMR (CDCl3, 300 MHz) δ 7.64 (s,
1 H), 7.62 (d, J ) 3.7 Hz, 1 H), 7.54 (d, J ) 4.9 Hz, 1 H), 7.49 (d,
J ) 8.3 Hz, 2 H), 7.17 (d, J ) 8.3 Hz, 2 H), 7.14-7.11 (m, 1 H),
4-Cyano-N-p-tolylbenzamide (3c): mp 177-179 °C; IR (KBr)
cm-1 3346, 2233, 1654, 1597, 1525, 1406, 1322, 1297, 1259, 814,
760, 630, 505; 1H NMR (CDCl3, 300 MHz) δ 7.96 (d, J ) 8.1 Hz,
2 H), 7.79 (bs, 1H), 7.78 (d, J ) 8.1 Hz, 2 H), 7.50 (d, J ) 8.1 Hz,
2 H), 7.19 (d, J ) 8.1 Hz, 2 H), 2.35 (s, 3 H); 13C NMR (DMSO-
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J. Org. Chem, Vol. 73, No. 7, 2008 2957

2.34 (s, 3 H). This is a known compound, and the spectral data are
identical to those reported in the literature.25
20772117 and 20621061) and Specialized Research Fund for
the Doctoral Program of Higher Education (No. 20050358021).
Supporting Information Available: 1H NMR spectra of 3a-k
and 13C NMR spectra of 3a,c,d,g-j. This material is available free
of charge via the Internet at http://pubs.acs.org.
Acknowledgment. We are grateful for the financial support
from National Natural Science Foundation of China (Nos.
(25) Katritzky, A. R.; Cai, C.; Singh, S. K. J. Org. Chem. 2006, 71,
3375.
JO800075T
2958 J. Org. Chem., Vol. 73, No. 7, 2008