Zinc(II)-catalyzed oxidative amidation of arylaldehydes with alkylamines under solvent-free conditions

Article abstract of DOI:10.1016/j.tetlet.2012.12.010

The first zinc-catalyzed oxidative amidation of arylaldehydes has been developed. Various amides were prepared in good yields under solvent-free and mild reaction conditions.

Full text of DOI:10.1016/j.tetlet.2012.12.010

Tetrahedron Letters 54 (2013) 1059–1062
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Zinc(II)-catalyzed oxidative amidation of arylaldehydes with alkylamines
under solvent-free conditions
Min Zhang a,b, Xiao-Feng Wu a,
⇑
a Leibniz-Institut für Katalyse e.V. an der Universität Rostock, Albert-Einstein-Strasse 29a, 18059 Rostock, Germany
b School of Chemical and Material Engineering, Jiangnan University, Wuxi 214122, China
a r t i c l e i n f o
a b s t r a c t
Article history:
The first zinc-catalyzed oxidative amidation of arylaldehydes has been developed. Various amides were
prepared in good yields under solvent-free and mild reaction conditions.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 29 October 2012
Revised 4 December 2012
Accepted 5 December 2012
Available online 11 December 2012
Keywords:
Zinc catalyst
Oxidative amidation
Aldehydes
Alkylamines
Solvent-free conditions
Drawing from the significant advantages of zinc salts including
inexpensiveness, abundance, and low toxicity, the exploration of
zinc derivatives as environmentally benign catalysts in organic
reactions has attracted considerable attention in the past decades.
In some aspects, zinc is considered as a desired alternative for toxic
or expensive transition-metal catalysts.1
materials that are widely available, these procedures are of poten-
tial value in industrial applications. However, many of these pro-
cesses require a key pre-treatment step to convert amines into
their salts owing to the nitrogen atom of amines which may com-
petitively occupy the coordination sites of metals that could de-
crease the catalyst activity.8 In some cases, these synthetic
protocols need high temperature or excessive amount of reagents
including organic solvents that would lead to tedious laboratory
procedures. Clearly, from the viewpoint of atom economy and
environmental concerns, the development of efficient and direct
methods for amide syntheses under mild conditions by using
amine compatible catalysts and meanwhile minimizing the waste
generation is of highly importance.
Considering various advantages of zinc catalysis and our contin-
uous research interests in developing zinc-catalyzed oxidation
reactions,9 we became interested in exploring a zinc catalyst for di-
rect oxidative amidation of aldehydes. Herein, for the first time we
present an efficient zinc-catalyzed oxidative amidation of arylalde-
hydes with alkylamines under solvent-free conditions.
Based on our previous investigations in zinc-catalyzed oxidative
esterification of aromatic aldehydes10a,b and some other oxidation
reactions, we initiated our studies by employing the standard reac-
tion conditions [catalyst: 10 mol % of ZnBr2; temperature: 80 °C;
reaction time: 16 h; solvent: pyridine; oxidant: 3 equiv of tert-
butyl hydroperoxide (TBHP)] in the synthesis of N-phenethylben-
zamide 3a from benzaldehyde 1a and 2-phenylethanamine 2a.
Gratifyingly, an almost quantitative yield was obtained upon
GC-analysis (Scheme 1, Eq. 1). Interestingly, the reaction under
Carboxamides constitute a significant important class of com-
pounds found in numerous bioactive products, polymers, and
pharmaceuticals.2 In addition, amides serve as useful building
blocks for the preparation of pharmaceuticals, agrochemicals, poly-
mers, etc.3 Owing to these extensive functions of amides, the
development of efficient methodologies for the construction of
amide skeleton has attracted significant interests from organic
chemists. Generally, amides can be prepared by conventional sub-
stitution reactions of amines with carboxylic acid derivatives, or by
the coupling of aryl/alkyl halides with amides.4 Additionally, the
classical name reactions (i.e., Ritter,5a Schmidt,5b Beckmann,5c
Ugi,5d Wolff,5e etc.) have also provided alternative routes to the
same end. During the past decades, a number of elegant methodol-
ogies were also developed to afford new accesses for amide
elaborations.6
Comparing to these significant contributions, the oxidative ami-
dation processes in which amines reacted with different alde-
hydes7 represent more directly and interesting unconventional
routes for the synthesis of carboxamides. Owing to the starting
⇑
Corresponding author. Tel.: +49 381 1281 343.
E-mail address: xiao-feng.wu@catalysis.de (X.-F. Wu).
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.12.010

1060
M. Zhang, X.-F. Wu / Tetrahedron Letters 54 (2013) 1059–1062
H
N
solvent-free conditions can still afford an excellent GC yield of 3a
(Scheme 1, Eq. 2). However, the isolated yield of 3a using sol-
vent-free conditions is much higher than the former manipulation
which is due to the product loss during the work-up procedure for
removing organic solvent. No amide was produced in the absence
of ZnBr2, but only the oxidation of aldehyde occurred. H2O2 as the
oxidant was tested as well, unfortunately, no desired amide was
detected.
Inspired by the above-described results, we then examined the
generality and limitation of this zinc-catalyzed oxidative amida-
tion protocol under solvent-free conditions. Initially, 2-phenyle-
thanamine 2a was employed in combination with various aryl
Ph
ZnBr2 (10 mol%), TBHP (3 equiv)
16h, 80 oC
+
Ph CHO
1a
Ph
Ph
(Eq. 1)
NH2
O
2a
3a
GC yiled: 95 %;
in pyridine (1 ml):
Isolated yield: 63 %
GC yiled: 90 %;
solvent-free conditions:
Isolated yield: 78 %
Scheme 1. Result comparison using solvent and solvent-free conditions.
Table 1
Zinc-catalyzed oxidative amidation of aldehydes into carboxamidesa
O
ZnBr2 (10 mol%), TBHP (3 equiv)
Alkyl
+
Ar CHO
Alkyl
NH2
Ar
N
H
80 oC, 16h, solvent-free
1
2
3
Entry
1
Aldehyde 1
Amine 2
Amide 3, yieldb (%)
O
2 NH2
Ph
Ph
N
H
CHO
2 Ph
2a
1a
3a, 78
O
2 NH2
Ph
N
H
2
Ph
CHO
CHO
1b
2a
2
3
4
5
3b, 66
PhO
O
2 NH2
Ph
2a
Ph
N
H
1c
PhO
3c, 70
O
2 NH2
Ph
N
H
2
Ph
N
1d
CHO
2a
N
3d, 71
Cl
Cl
O
2 NH2
Ph
N
2
Ph
CHO
CHO
H
2a
1e
Cl
Cl
3e, 66
F3C
O
2 NH2
Ph
N
H
2
Ph
2a
6
7
1f
F3C
3f, 82
O
2 NH2
Ph
N
H
2
Ph
CHO
2a
1g
3g, 55

M. Zhang, X.-F. Wu / Tetrahedron Letters 54 (2013) 1059–1062
1061
Table 1 (continued)
Entry
Aldehyde 1
Amine 2
Amide 3, yieldb (%)
H
N
O
2 NH2
Ph
N
H
O
2
Ph
O
2a
CHO
8
N
H
1h
3h, 90
O
O
2 NH2
Ph
N
H
2
Ph
2a
CHO
9
1i
1j
3i, 62
2 NH2
Ph
N
H
2
Ph
Ph
2a
CHO
CHO
10
3j, 58
NC
O
2 NH2
Ph
N
2
H
2a
11
12
1k
NC
3k, 81
O
4 NH2
N
H
4
N
1d
CHO
2b
N
3l, 64
NC
O
4 NH2
N
H
4
CHO
2b
2c
2c
13
14
15
1k
NC
3m, 78
O
3 NH2
N
3
CHO
H
1a
3n, 56
PhO
O
3 NH2
N
3
CHO
H
1c
PhO
3o, 75
O
CHO
NH2
N
H
16
1a
2d
3p, <10
a
Reaction conditions: unless otherwise specified, all reactions were carried out with 1 (1 mmol), 2 (1.1 mmol), and ZnBr2 (0.1 mmol), TBHP (3 equiv; 70% solution in water)
at 80 °C for 16 h.
b
Isolated yield.

1062
M. Zhang, X.-F. Wu / Tetrahedron Letters 54 (2013) 1059–1062
Catal. 2006, 348, 1029–1032; (i) Bandini, M.; Melucci, M.; Piccinelli, F.; Sinisi,
R.; Tommasi, S.; Umani-Ronchi, A. Chem. Commun. 2007, 4519–4521; (j)
Inagaki, T.; Yamada, Y.; Phong, L. T.; Furuta, A.; Ito, J.-i. .; Nishiyama, H. Synlett
2009, 253–256; (k) Gajewy, J.; Kwit, M.; Gawronski, J. Adv. Synth. Catal. 2009,
351, 1055–1063; (l) Das, S.; Addis, D.; Zhou, S.; Junge, K.; Beller, M. J. Am. Chem.
Soc. 2010, 132, 1770–1771; (m) Marinos, N. A.; Enthaler, S.; Driess, M.
ChemCatChem 2010, 2, 846–853; (n) Enthaler, S.; Eckhardt, B.; Inoue, S.;
Irran, E.; Driess, M. Chem. Asian J. 2010, 5, 2027–2035; (o) Enthaler, S.; Schröder,
K.; Inoue, S.; Eckhardt, B.; Junge, K.; Beller, M.; Driess, M. Eur. J. Org. Chem. 2010,
4893–4901; (p) Enthaler, S. Catal. Lett. 2011, 141, 55–61; (q) Enthaler, S. Catal
Sci. Technol. 2011, 1, 104–110; (r) Enthaler, S.; Inoue, S. Chem. Asian J. 2012, 7,
169–175; (s) Enthaler, S.; Weidauer, M. Chem. Eur. J. 2012, 18, 1910–1913.
2. (a) Kung, P. P.; Huang, B. W.; Zhang, G.; Zhou, J. Z.; Wang, J.; Digits, J. A.;
Skaptason, J.; Yamazaki, S.; Neul, D.; Zientek, M.; Elleraas, J.; 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; (b) Armelin, E.; Franco, L.; Rodriguez-Galan, A.;
Puiggali, J. Macromol. Chem. Phys. 2002, 203, 48–58; (c) Glomb, M. A.; Pfahler, C.
J. Biol. Chem. 2001, 276, 41638–41647.
aldehydes, to synthesise different substituted amides. As shown in
Table 1, all the reactions proceeded smoothly and gave desired
products in good to excellent isolated yields (Table 1, entries 1–
11). Electron-withdrawing and -donating substitutents including
meta position (such as –CN, amide group) on the aryl ring of alde-
hydes were tolerated, and the substituents have significant influ-
ence in the formation of the products. Specifically, arylaldehydes
bearing an electron-withdrawing group gave relatively higher
product yields (Table 1, entries 6, 8, 11, 13) than that of electron-
rich ones. The phenomenon can be explained that the addition of
amine to more electrophilic carbonyl group could favorably form
an alpha-hydroxyl amine intermediate, which is in agreement with
the mechanism proposed in the literature.7 Subsequently, other
representative alkylamines (including n-hexanamine 2b, n-butan-
amine 2c, and cyclohexanamine 2d) were tested to generate differ-
ent N-alkylated amides. The results showed that all the linear
alkylamines can be converted into the corresponding amides in
an efficient manner (Table 1, entries 12–15). However, the bulkier
cyclohexanamine gave only small amount of the expected product,
which is associated with the influence of steric hindrance (Table 1,
entry 16). Interestingly, heteroaryl aldehydes (such as picolinalde-
hyde 1d) could also be employed as a coupling partner (Table 1,
entries 4 and 12), the resulting product might be applicable as a li-
gand for metal catalysis or complex preparations.11 As reported7b
the reaction of aldehydes with secondary amines can give the cor-
responding amides in the presence of H2O2 without any catalyst.
Under this background, we did not test secondary amines under
our reaction conditions. Additionally, pentanal as an example of al-
kyl aldehydes was checked under our standard conditions, but no
amide was formed.
3. (a) Wang, G. W.; Yuan, T. T.; Li, D. D. Angew. Chem., Int. Ed. 2011, 50, 1380–1383.
Angew. Chem. 2011, 123, 1416–1419; (b) Zhang, X. X.; Teo, W. T.; Chan, P. W. H.
J. Organomet. Chem. 2011, 696, 331–337.
4. (a) Gnanaprakasam, B.; Milstein, D. J. Am. Chem. Soc. 2011, 133, 1682–1685; (b)
Zare, A.; Hasaninejad, A.; Moosavi-Zare, A. R.; Parhami, A.; Khalafi-Nezhad, A.
Asian J. Chem. 2009, 21, 1090–1096; (c) Hartwig, J. F. Synlett 2006, 1283–1294;
(d) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131–209; (e)
Buchwald, S. L.; Mauger, C.; Mignani, G.; Scholz, U. Adv. Synth. Catal. 2006, 348,
23–39; (f) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41, 1440–1449; (g)
Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; (h) Surry, D. S.; Buchwald, S.
L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361. Angew. Chem. 2008, 120, 6438–
6461.
5. (a) Ritter, J. J.; Minieri, P. P. J. Am. Chem. Soc. 1948, 70, 4045–4048; (b) Schmidt,
R. F. Ber. Dtsch. Chem. Ges. 1924, 57, 704; (c) Beckmann, E. Chem. Ber. 1886, 89,
988; (d) Ugi, I. Angew. Chem., Int. Ed. 1962, 74, 9; (e) Wolff, L. Justus. Liebigs. Ann.
Chem. 1912, 384, 25.
6. (a) Zhang, M.; Imm, S.; Bähn, S.; Neubert, L.; Neumann, H.; Beller, M. Angew.
Chem., Int. Ed. 2012, 51, 3905–3909; (b) Miyasaka, M.; Hirano, K.; Satoh, T.;
Kowalczyk, R.; Bolm, C.; Miura, M. Org. Lett. 2011, 13, 359–361; (c) Xiao, B.;
Gong, T. J.; Xu, J.; Liu, Z. J.; Liu, L. J. Am. Chem. Soc. 2011, 133, 1466–1474; (d)
Wang, Y.; Zhu, D. P.; Tang, L.; Wang, S. J.; Wang, Z. Y. Angew. Chem., Int. Ed.
2011, 50, 8917–8921; (e) Driller, K. M.; Prateeptongkum, S.; Jackstell, R.; Beller,
M. Angew. Chem., Int. Ed. 2011, 50, 537–541; (f) Gnanaprakasam, B.; Milstein, D.
J. Am. Chem. Soc. 2011, 133, 1682–1685; (g) Wu, X.-F.; Neumann, H.; Beller, M.
Chem. Asian J. 2010, 5, 2168–2172; (h) Neumann, J. J.; Rakshit, S.; Droge, T.;
Glorius, F. Angew. Chem., Int. Ed. 2009, 48, 6892–6895; (i) Kurokawa, T.; Kim,
M.; Du Bois, J. Angew. Chem., Int. Ed. 2009, 48, 2777–2779; (j) Zare, A.;
Hasaninejad, A.; Moosavi-Zare, A. R.; Parhami, A.; Khalafi-Nezhad, A. Asian. J.
Chem. 2009, 21, 1090–1096; (k) Marion, N.; Nolan, S. P. Acc. Chem. Res. 2008, 41,
1440–1449; (l) Hartwig, J. F. Acc. Chem. Res. 2008, 41, 1534–1544; (m) Surry, D.
S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338–6361; (n) Kantchev, E.
A. B.; O’Brien, C. J.; Organ, M. G. Angew. Chem., Int. Ed. 2007, 46, 2768–2813; (o)
Li, Z. G.; Capretto, D. A.; Rahaman, R. O.; He, C. J. Am. Chem. Soc. 2007, 129,
12058–12059; (p) He, L.; Yu, J.; Zhang, J.; Yu, X. Q. Org. Lett. 2007, 9, 2277–2280.
7. For selected examples on oxidative amidation, see: (a) Ghosh, S. C.; Ngiam, J. S.
Y.; Chai, C. L. L.; Seayad, A. M.; Dang, T. T.; Chen, A. Adv. Synth. Catal. 2012, 354,
1407–1412; (b) Tank, R.; Pathak, U.; Vimal, M.; Bhattacharyya, S.; Pandey, L. K.
Green Chem. 2011, 13, 3350–3354; (c) Allen, C. L.; Davulcu, S.; Williams, J. M. J.
Org. Lett. 2010, 12, 5096–5099; (d) Dam, J. H.; Osztrovszky, G.; Nordstrom, L. U.;
Madsen, R. Chem. Eur. J. 2010, 16, 6820–6827; (e) Woo, W. J.; Li, C. J. J. Am. Chem.
Soc. 2006, 128, 13064–13065; (f) Liu, Z.; Zhang, J.; Chen, S.; Shi, E.; Xu, Y.; Wan,
X. Angew. Chem., Int. Ed. 2012, 51, 3231–3235; (g) Porcheddu, A.; De Luca, L.
Adv. Synth. Catal. 2012, 354, 2949–2953; (h) Reddy, K. R.; Maheswari, C. U.;
Venkateshwar, M.; Kantam, M. L. Eur. J. Org. Chem. 2008, 3619–3622; (i) Cadoni,
R.; Porcheddu, A.; Giacomelli, G.; De Luca, L. Org. Lett. 2012, 14, 5014–5017.
8. (a) Zhang, M.; Imm, S.; Bähn, S.; Neumann, H.; Beller, M. Angew. Chem., Int. Ed.
2011, 50, 11197–11201. Angew. Chem. 2011, 123, 11393–11397; (b) Yang, W.;
Fu, H.; Song, Q. J.; Zhang, M.; Ding, Y. Q. Organometallics 2011, 30, 77–83; (c)
Jones, M. B.; Newell, B. S.; Hoffert, W. A.; Hardcastle, K. I.; Shores, M. P.;
MacBeth, C. E. Dalton Trans. 2010, 39, 401–410; (d) Zhang, Z.; Leitch, D. C.; Lu,
M.; Patrick, B. O.; Schafer, L. L. Chem. Eur. J. 2007, 13, 2012–2022; (e) Hoerter, J.
M.; Otte, K. M.; Gellman, S. H.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 5177–
5183; (f) Thomson, R. K.; Bexrud, J. A.; Schafer, L. L. Organometallics 2006, 25,
4069–4071.
In summary, we have developed a zinc-catalyzed oxidative ami-
dation of arylaldehydes that allows directly employing alkylamines
under solvent-free conditions. Compared to previously known oxi-
dative amidation catalysts, ZnBr2 is comparably inexpensive and
can be conveniently used without special precautions. A wide
range of products bearing different functionalized groups is conve-
niently accessible in reasonable to excellent isolated yields. The
significant advantages of this synthetic protocol make it a practical
and environmentally benign pathway to synthesize N-alkylated
arylamides, which is highly important for organic chemistry.
Acknowledgments
The financial support from the state of Mecklenburg-Vorpomm-
ern and the Bundesministerium für Bildung und Forschung (BMBF)
is gratefully acknowledged. The authors also thank the support and
general advice from Professor Dr. Matthias Beller and Dr. Helfried
Neumann (LIKAT).
Supplementary data
Supplementary data associated with this article can be found, in
the
online
version,
at
http://dx.doi.org/10.1016/
j.tetlet.2012.12.010.
9. For reviews on zinc-catalyzed reactions, see: (a) Wu, X.-F. Chem. Asian J. 2012,
7, 2502–2509; (b) Wu, X.-F.; Neumann, H. Adv. Synth. Catal. 2012, 354, 3141–
3160.
10. (a) Wu, X.-F. Chem. Eur. J. 2012, 18, 8912–8915; (b) Wu, X.-F. Tetrahedron Lett.
2012, 53, 3397–3399; (c) Wu, X.-F. Tetrahedron Lett. 2012, 53, 4328–4331; (d)
Song, Z.-Z.; Gong, J.-L.; Zhang, M.; Wu, X.-F. Asian J. Org. Chem. 2012, 1, 214–
217; (e) Wu, X.-F. Tetrahedron Lett. 2012, 53, 6123–6126; (f) Wu, X.-F.; Bheeter,
C. B.; Neumann, H.; Dixneuf, P. H.; Beller, M. Chem. Commun. 2012, 48, 12237–
12239.
References and notes
1. (a) Bette, V.; Mortreux, A.; Lehmann, C. W.; Carpentier, J.-F. Chem. Commun.
2003, 332–333; (b) Bette, V.; Mortreux, A.; Ferioli, F.; Martelli, G.; Savoia, D.;
Carpentier, J.-F. Eur. J. Org. Chem. 2004, 3040–3045; (c) Bette, V.; Mortreux, A.;
Savoia, D.; Carpentier, J.-F. Tetrahedron 2004, 60, 2837–2842; (d) Mastranzo, V.
M.; Quinterno, L.; Anaya de Parrodi, C.; Juaristi, E.; Walsh, P. J. Tetrahedron
2004, 60, 1781–1789; (e) Ushio, H.; Mikami, K. Tetrahedron Lett. 2005, 46,
2903–2906; (f) Bette, V.; Mortreux, A.; Savoia, D.; Carpentier, J.-F. Adv. Synth.
Catal. 2005, 347, 289–302; (g) Gérard, S.; Pressel, Y.; Riant, O. Tetrahedron:
Asymmetry 2005, 16, 1889–1891; (h) Park, B.-M.; Mun, S.; Yun, J. Adv. Synth.
11. Yang, W.; Fu, H.; Song, Q. J.; Zhang, M.; Ding, Y. Q. Organometallics 2011, 30, 77–
83.