Dehydrogenative amide synthesis from alcohol and amine catalyzed by hydrotalcite-supported gold nanoparticles

Article abstract of DOI:10.1016/j.tetlet.2012.04.048

Hydrotalcite-supported nano-gold (Au/HT) was found to be a highly efficient heterogeneous catalyst for the dehydrogenative synthesis of amide from alcohol and amine. Amines and alcohols with different structures could be converted into the amides under mild reaction conditions with up to 98% isolated yields. Mechanism exploration suggested that ester might be the reaction intermediate.

Full text of DOI:10.1016/j.tetlet.2012.04.048

Tetrahedron Letters 53 (2012) 3178–3180
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Dehydrogenative amide synthesis from alcohol and amine catalyzed
by hydrotalcite-supported gold nanoparticles
Jiangling Zhu a,b,c, Yan Zhang a, Feng Shi a, , Youquan Deng a
⇑
a Centre for Green Chemistry and Catalysis, Lanzhou Institute of Chemical Physics, CAS, Lanzhou 730000, China
b Graduate University of Chinese Academy of Sciences, Beijing 100049, China
c State Key Laboratory of Applied Organic Chemistry and Department of Chemistry, Lanzhou University, Lanzhou, 730000, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Hydrotalcite-supported nano-gold (Au/HT) was found to be a highly efficient heterogeneous catalyst for
the dehydrogenative synthesis of amide from alcohol and amine. Amines and alcohols with different
structures could be converted into the amides under mild reaction conditions with up to 98% isolated
yields. Mechanism exploration suggested that ester might be the reaction intermediate.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 12 March 2012
Revised 5 April 2012
Accepted 12 April 2012
Available online 21 April 2012
Keywords:
Amides
Gold
Heterogeneous catalysis
Amines
Alcohols
The amide linkage is a common and very important functional
group which contributes to the special properties of peptides, pro-
teins, beta-lactam antibiotics, and numerous synthetic polymers.1
Amides are typically synthesized by using activated carboxylic
acids and amines, which often require stoichiometric amounts of
coupling reagents and produce toxic chemical waste.2 Recently,
several groups have reported the amide synthesis from alcohols
with amines using homogeneous Ru3, Rh4 and heterogeneous
Ag5, Au6 based catalytic systems.7 However, high reaction temper-
ature or hydrogen acceptor was normally required in order to gain
good result. The development of efficient heterogeneous catalyst
for amidation reaction under mild reaction conditions is still
imperative. Here, we report our new results about hydrotalcite8
supported nano-gold (Au/HT)9 catalyzed amidation reaction of
alcohol with amine in the absence of hydrogen receptor and organ-
ic ligands, Scheme 1.
these results clearly indicated that a catalyst contains Au0 nano-
particle immobilized on the surface of crystalline HT was obtained.
Initially, the amidation reaction of morpholine with benzyl
alcohol in the absence of organic ligand was explored using differ-
ent catalysts (Table 1). Among the catalysts examined, Au/HT
O
H
N
Au/HT
R1
+
R3
OH
R1
R2
N
R3 + H2O + H2
R2
Scheme 1. Dehydrogenative amide synthesis.
The gold-based catalysts were characterized by XRD, XPS, and
BET. The XRD characterization suggested that the gold was highly
dispersed and no crystal diffraction patterns were observable. TEM
measurement showed that the average particle size of the gold is
2–3 nm, Figure 1. XPS analysis revealed the formation of metallic
gold with a binding energy of 83.9 eV for the Au 4f7/2. BET analysis
showed that the BET surface area of the Au/HT is 93.4 m2/g. All
⇑
Corresponding author. Tel.: +86 931 4968142; fax: +86 931 8277088.
E-mail address: fshi@licp.cas.cn (F. Shi).
Figure 1. TEM, HAADF images and Au particle size of Au/HT.
0040-4039/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2012.04.048

J. Zhu et al. / Tetrahedron Letters 53 (2012) 3178–3180
3179
Table 1
Table 3
Catalyst screening and reaction condition optimizationa
Reactions of morpholine with different alcoholsa
Yieldb (%)
H
N
Entry
Alcohol
T(°C)
t(h)
O
3
OH
OH
+
N
1
2
90
24
94
97
O
1
O
2
OH
OH
90
80
36
36
Entry Catalysts
Loading/mol (%) Con. (%) of 1b Yield (%) of 3c
1
2
3
4
5
6
3.7wt%Au/HT
3.1wt%Au/MgO
4.3wt%Au/Al2O3 2.2
0.18wt%Pd/HT
3.8wt%Ru/HT
HT
3.7wt%Au/HT
3.7wt%Au/HT
3.7wt%Au/HT
1.9
1.6
>99
79
97
0
0
0
57
99
98
99
42
82
0
0
0
4
97
80
3
4
81
87
0.17
OH
3.8
——
1.9
1.9
1.9
90
80
24
36
F3C
7d
8e
9f
OH
5
85
a
0.5 mmol morpholine, 1.0 mmol benzyl alcohol, 50 mg catalyst, 0.6 mmol KOt-
Bu, 5 mL o-xylene, 90 °C, 24 h, Ar.
O
O
S
b
c
d
e
f
The conversion was estimated by GC-FID according to the peak area.
The yield of 3 was determined by GC using biphenyl as internal standard.
The reaction was performed under base free conditions.
The catalyst was recovered and reused at the 2rd run.
25 °C, O2, 3 h.
OH
OH
6
7
80
90
36
36
86
79
OH
OH
Table 2
8
9
90
90
24
24
98
93
Benzyl alcohol amidation with different aminesa
F
Entry
1
Amine
T(°C)
t(h)
24
Yieldb (%)
85
H
N
90
Cl
Cl
O
H
2
3
4
5
6
7c
NH
NH
NH
NH
90
90
90
90
90
90
24
24
24
24
24
24
96
94
81
81
79
76
10
11
12
13
80
90
90
90
36
24
24
24
89
80
96
94
O
N
O
OH
O
O
OH
N
OH
NH
NH
N
S
HN
HN
14
90
36
78
8c
80
36
72
OH
OH
NH
O
15
16
17
90
90
80
36
48
24
90
92
60
9
90
70
24
36
76
65
NH
10
BnNH2
a
0.5 mmol amine, 1.0 mmol benzyl alcohol, 50 mg Au/HT, 0.6 mmol KOt-Bu,
5 mL o-xylene, Ar.
Isolated yield.
OH
b
c
0.25 mmol amine.
OH
a
0.5 mmol morpholine, 1.0 mmol alcohol, 50 mg Au/HT, 0.6 mmol KOt-Bu, 5 mL
o-xylene, Ar.
Isolated yield.
10
exhibited the highest catalytic activity with 99% yield (entry 1).
Under the same conditions, the applying of Au/MgO and Au/Al2O3
gave 42% and 82% yields respectively (entries 2 and 3). No amide
formed if using Pt/HT, Ru/HT, and HT as catalysts (entries 4–6).
The addition of base was also necessary in order to gain high yield.
Only 4% amidation product was formed under base free conditions
(entry 7). The catalyst Au/HT was easy to be recovered and reused,
and 97% yield was maintained at the 2nd run (entry 8). However,
only 54% yield was obtained at the 3rd run. Therefore, the catalyst
stability should be further improved. It is noteworthy that the
b
reaction could progress well at room temperature under oxygen
atmosphere with 80% yield.
By applying the optimized reaction condition, the amidation
reactions of benzyl alcohol with different amines were explored
(Table2). First, theamidationreactionsofbenzylalcoholwithseveral
cyclic secondary amines such as pyrrolidine, piperidine, morpholine,

3180
J. Zhu et al. / Tetrahedron Letters 53 (2012) 3178–3180
H
N
Supplementary data
OH
O
R1
R2
- H2
base
R2
R2
Supplementary data associated with this article can be found, in
theonlineversion, at http://dx.doi.org/10.1016/j.tetlet.2012.04.048.
R
R
N
R1
R
R
N
R1
Previous works
H
N
- H2
References and notes
R
OH
R1
O
R2
R
O
R
OH
1. Greenberg, A.; Breneman, C. M.; Liebman, J. F. The Amide Linkage: Structural
Significance in Chemistry, Biochemistry, and Materials Science; Wiley-VCH:
Weinheim, 2002.
O
OH
- H2
This work
Scheme 2. Mechanism for Au/HT catalyzed amide formation.
R
R
O
2. Han, S.-Y.; Kim, Y.-A. Tetrahedron 2004, 60, 2447–2467.
3. (a) Naota, T.; Murahashi, S.-I. Synlett 1991, 1991, 693–694; (b) Gunanathan, C.;
Ben-David, Y.; Milstein, D. Science 2007, 317, 790–792; (c) Nordstrom, L. U.;
Vogt, H.; Madsen, R. J. Am. Chem. Soc. 2008, 130, 17672–17673; (d) Zhang, Y.;
Chen, C.; Ghosh, S. C.; Li, Y. X.; Hong, S. H. Organometallics 2010, 29, 1374–1378;
(e) Watson, A. J. A.; Maxwell, A. C.; Williams, J. M. J. Org. Lett. 2009, 11, 2667–
2670; (f) Zeng, H. X.; Guan, Z. B. J. Am. Chem. Soc. 2011, 133, 1159–1161; (g)
Ghosh, S. C.; Muthaiah, S.; Zhang, Y.; Xu, X. Y.; Hong, S. H. Adv. Synth. Catal.
2009, 351, 2643–2649; (h) Dam, J. H.; Osztrovszky, G.; Nordstrom, L. U.;
Madsen, R. Chem. Eur. J. 2010, 16, 6820–6827; (i) Ghosh, S. C.; Hong, S. H. Eur. J.
Org. Chem. 2010, 4266–4270; (j) Muthaiah, S.; Ghosh, S. C.; Jee, J. E.; Chen, C.;
Zhang, J.; Hong, S. H. J. Org. Chem. 2010, 75, 3002–3006; (k) Nova, A.; Balcells,
D.; Schley, N. D.; Dobereiner, G. E.; Crabtree, R. H.; Eisenstein, O.
Organometallics 2010, 29, 6548–6558; (l) Zhang, J. A.; Senthilkumar, M.;
Ghosh, S. C.; Hong, S. H. Angew. Chem., Int. Ed. 2010, 49, 6391–6395; (m) Chen,
C.; Zhang, Y.; Hong, S. H. J. Org. Chem. 2011, 76, 10005–10010; (n) Schley, N. D.;
Dobereiner, G. E.; Crabtree, R. H. Organometallics 2011, 30, 4174–4179.
4. Zweifel, T.; Naubron, J.-V.; Grützmacher, H. Angew. Chem., Int. Ed. 2009, 48,
559–563.
1-methylpiperazine, 1-ethylpiperazine, and 4-methylpiperidine
were tried (entries 1–6).
All the reactions progressed smoothly and the isolated yields to
the corresponding amides were 79–96%. Good yield was obtained
in the dehydrogenative amidation of benzyl alcohol with 1,2,3,4-
tetrahydroisoquinoline, too (entry 7). Double amidation reactions
could be obtained if piperazine and 1,3-di-4-piperidylpropane
were employed as starting materials (entries 8 and 9). The yields
of the target products were 76% and 72%. In the end, the amidation
reactions of benzyl alcohol with primary and non-cyclic secondary
amines, such as aniline, dodecylamine, and di-n-butylamine, were
tested. However, amines and imines were observed as the major
products except that using benzyl amine, which resulted in 65%
amide yield (entry 10).
5. Shimizu, K.; Ohshima, K.; Satsuma, A. Chem. Eur. J. 2009, 15, 9977–9980.
6. (a) Wang, Y.; Zhu, D.; Tang, L.; Wang, S.; Wang, Z. Angew. Chem., Int. Ed. 2011,
50, 8917–8921; (b) Soule, J.-F.; Miyamura, H.; Kobayashi, S. J. Am. Chem. Soc.
2011, 133, 18550–18553; (c) Klitgaard, S. K.; Egeblad, K.; Mentzel, U. V.; Popov,
A. G.; Jensen, T.; Taarning, E.; Nielsen, I. S.; Christensen, C. H. Green Chem. 2008,
10, 419–423.
The amidation reactions of different alcohols with morpholine
were investigated as shown in Table 3. First, the amidation reac-
tions of benzylic alcohols with different substituting groups were
explored and 79–98% yields were achieved (entries 1–12). Clearly,
the position and property of the substituting group did not affect
the activity of alcohols remarkably. The presence of heteroatoms
normally results in specific properties in the compounds. So herein
we tried the amidation reactions of several heterocyclic alcohols.
To our delight, the amidation reactions of 3-pyridinylmethanol,
3-thiophenylmethanol, and 2-furanylmethanol could be realized
successfully with 78–94% yields (entries 13–15). Importantly,
60–92% yields were achieved for aliphatic alcohols as acylating re-
agents (entries 16 and 17). These results suggested that Au/HT
showed high catalytic activities for the coupling of benzylic, het-
eroatom-containing and especially aliphatic alcohols, and amines
to synthesize amides.
7. For reviews, see: (a) Allen, C. L.; Williams, J. M. J. Chem. Soc. Rev. 2011, 40, 3405–
3415; (b) Chen, C.; Hong, S. H. Org. Biomol. Chem. 2011, 9, 20–26; (c)
Dobereiner, G. E.; Crabtree, R. H. Chem. Rev. 2010, 110, 681–703.
8. General procedure for the preparation of HT: Mg/Al HT (hydrotalcite) was
prepared as follows (Tsuji, A.; Rao, K. T. V.; Nishimura, S.; Takagaki, A.; Ebitani,
K. ChemSuschem 2011, 4, 542-548.): Mg(NO3)2Á6H2O (30 mmol) and
Al(NO3)3Á6H2O (10 mmol) were dissolved in water (100 mL). The aqueous
solution containing Mg and Al ions was added to an alkaline solution composed
of Na2CO3Á10H2O (30 mmol) and water (100 mL) in 1 h at room temperature.
During the addition of Mg and Al ions, the pH value of the solution was
maintained at 10 by adding a 1 M aq solution of NaOH. After aging for 1 h at
65 °C, the white solid was filtered and washed with deionized water (2 L) to
remove sodium ions. The obtained solid was dried at 100 °C in air overnight.
9. General procedure for the preparation of Au/HT: Au/HT catalyst was prepared by
wet-impregnation. 400 mg HT was added to 4.8 mL of HAuCl4 aqueous solution
(24 mM). After stirring for 2 min, the pH value of the solution was maintained
at 10 by adding aqueous NH3 (ꢀ25 wt%), and the resulting mixture was stirred
at room temperature for 12 h. Then, it was centrifuged and washed twice with
100 mL deionized water. Au/HT was obtained after the solid was dried at 80 °C
for 1 h and reduced with hydrogen at 150 °C for 1 h.
Following, the reaction mechanism was explored through the
reactions of morpholine with benzaldehyde and benzyl benzoate.
Interestingly, 91% amide formed in 8 h if using benzyl benzoate
as starting material but only 29% amide was observed if benzalde-
hyde was employed. Possibly, the presence of alcohol promotes the
reaction significantly via the formation of benzyl benzoate. Thus
the amidation reaction presumably follows the mechanism in
Scheme 2.3b,3c
In summary, a simple Au/HT was prepared for the dehydroge-
native amidation of alcohols. In general, good to excellent yields
are achieved using amines and alcohols containing various func-
tional groups as starting materials.
10. General procedure for the dehydrogenative amide synthesis from amine and
alcohol: All the reactions were carried out in a multi-reactor (Carousel 12
station, RADLEYS). Typically, 0.5 mmol morpholine (43 mg), 1.0 mmol benzyl
alcohol (108 mg), 50 mg Au/HT (1.9 mol % Au), and 5 mL o-xylene were added
to a 40 mL glass vessel. Then, the reaction mixture was stirred (310 rpm) at
90 °C under argon. After 24 h, it was cooled down to room temperature.
ꢀ20 mL ethyl acetate was added to dissolve the reaction mixture and filtrated
with celite to remove the solids. Then the ethyl acetate and solvent were
removed under vacuum and a yellow liquid was obtained. It was further
purified using column chromatography (ethyl acetate / petroleum ether = 2/3,
v/v; Silica Gel: 200–300 mesh; Rf = 0.17) to obtain the pure product as a white
solid. m.p. 69–70 °C. 1H NMR (400 MHz, CDCl3, ppm): d 7.42 (s, 5H), d 3.46–
3.79 (m, 8H) 13C NMR (100 MHz, CDCl3, ppm): d 170.4, 135.2, 129.8, 128.5,
127.0, 66.8, 48.2, 42.5.
Acknowledgments
This work was financially supported by the National Natural
Science Foundation of China (21073208) and the Chinese Academy
of Sciences.