An efficient synthesis of amides from alcohols and azides catalyzed by a bifunctional catalyst Au/DNA under mild conditions

Article abstract of DOI:10.1039/c3gc42485e

A novel Au/DNA-catalyzed amidation from alcohols and azides was developed under mild conditions. Taking advantage of the water-soluble reversibility of this catalyst, the transformation could be carried out smoothly in water and the catalyst could be recovered and reused by a simple phase separation. This amidation reaction unitized the hydrogen transfer process and the oxidative coupling process synergistically in an atom economical and environmentally benign synthesis. the Partner Organisations 2014.

Full text of DOI:10.1039/c3gc42485e

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An efficient synthesis of amides from alcohols and
azides catalyzed by a bifunctional catalyst Au/DNA
under mild conditions†
Cite this: Green Chem., 2014, 16,
2443
Received 6th December 2013,
Accepted 30th January 2014
Xuefeng Guo,‡ Lin Tang,‡ Yu Yang, Zhenggen Zha and Zhiyong Wang*
DOI: 10.1039/c3gc42485e
www.rsc.org/greenchem
A novel Au/DNA-catalyzed amidation from alcohols and azides was
developed under mild conditions. Taking advantage of the water-
soluble reversibility of this catalyst, the transformation could be
carried out smoothly in water and the catalyst could be recovered
and reused by a simple phase separation. This amidation reaction
unitized the hydrogen transfer process and the oxidative coupling
process synergistically in an atom economical and environmentally
benign synthesis.
Scheme 1 Au/DNA-catalyzed amidation from alcohols and azides.
The amide bond is one of the most fundamental functional
groups due to its widespread occurrence in the pharmaceutical
industry, materials science, and chemical biology.1 Traditional
approaches to amide synthesis involve the condensation of car-
boxylic acids or activated carboxylic acid derivatives (acid anhy-
drides and acid halides) with amines under harsh conditions,
accompanied with a large amount of waste.2 From the view-
point of atom economy and environmental concern, mild and
waste-free methods for the synthesis of amides are in high
demand. Recently, several innovative approaches have been
developed, which include direct amidation of alcohols,3 alde-
hydes,4 alkynes,5 thioesters6 and α-bromonitroalkanes7 with
amines and cross-coupling of acyl and aminyl radicals.8 All of
these systems employ amines as the starting materials.
Azides as another important nitrogen source for amide syn-
thesis have rarely been reported except for the Schmidt9 and
Boyer10 reactions. Very recently, two new base-mediated amida-
tion reactions of aldehydes with azides have been developed.11
However, aryl azides were ineffective starting materials for the
synthesis of the amides in Manetsch’s work.11a In Moses’s
work,11b the substrates used were azides bearing electron-with-
drawing groups. Other Ru- and Rh-catalyzed reactions for
amide synthesis have been successfully reported.12 Neverthe-
less, toxic solvents, high reaction temperatures, specific
directing groups or long reaction times were necessary in
these reactions. Because of the advantages of high catalytic
efficiency and easy recycling, heterogeneous catalysts have
been receiving more and more attention.13 Natural DNA has
been applied successfully as a template for metal nanoparti-
cles by our group for organic reactions.3c,14 Herein, we unveil a
straightforward protocol starting from alcohols and azides to
synthesize amides in water under the catalysis of gold nano-
particles immersed in DNA (Au/DNA) (Scheme 1).
Initially, Au/DNA was prepared according to the method
reported previously.3c,14a We then employed it directly for
amidation using benzyl alcohol (1a) and azidobenzene (2a) as
the model substrates (Table 1). The influence of the base on
the reaction was first investigated. Generally, strong bases
favored this reaction (entries 1–5) while lower yields were
obtained when weaker bases were employed (entries 6–9).
Moreover, KOH offered the highest yield among these bases
(entry 5). In the absence of base, no desired product was
observed (entry 10). Furthermore, the results showed that 1
equivalent of KOH was the optimal dosage (entries 11–12).
Subsequently, the ratio of the substrates and the reaction
temperature were investigated. The experimental results indi-
cated that a 2 : 1 ratio of 1a/2a at 50 °C afforded the highest
yield (entry 13). Also, the reaction could take place in either an
air or nitrogen atmosphere (entries 17 and 18).
Hefei National Laboratory for Physical Sciences at Microscale, CAS Key Laboratory of
Soft Matter Chemistry & Collaborative Innovation Center of Suzhou Nano Science
and Technology, University of Science and Technology of China, Hefei, 230026,
P. R. China. E-mail: zwang3@ustc.edu.cn; Fax: (+86) 551-360-3185
†Electronic supplementary information (ESI) available: Experimental details,
Afterwards, a screening of the catalysts was conducted
(Table 2). In the absence of a catalyst, no desired product was
observed (entry 9). DNA-templated metal catalysts, such as
characterization of catalysts and characterization of products. See DOI: 10.1039/
c3gc42485e
‡These authors contributed equally to this work.
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Table 1 Optimization of the reaction conditionsa
Table 3 Synthesis of amides from various alcohols and azidobenzenea
Entry
1a : 2a
Base (equiv.)
T (°C)
Yieldb (%)
Entry
Product
Yieldb (%)
1
2
3
4
5
6
7
8
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
3 : 1
2 : 1
1 : 1
2 : 1
2 : 1
2 : 1
2 : 1
C4H9OLi (1.0)
C4H9OK (1.0)
LiOH·H2O (1.0)
NaOH (1.0)
KOH (1.0)
Li2CO3 (1.0)
Na2CO3 (1.0)
K2CO3 (1.0)
Cs2CO3 (1.0)
No base
KOH (0.75)
KOH (1.5)
KOH (1.0)
KOH (1.0)
KOH (1.0)
50
50
50
50
50
50
50
50
50
50
50
50
50
50
40
60
50
50
57
69
74
58
1
2
3
4
5
6
7
8
PhCH2OH
3aa
3ba
3ca
3da
3ea
3fa
3ga
3ha
3ia
3ja
3ka
3la
3ma
3na
85
81
73
78
71
57
80
76
83
59
67
73
69
72
4-MeOC6H4CH2OH
3-MeOC6H4CH2OH
4-MeC6H4CH2OH
3-MeC6H4CH2OH
2-MeC6H4CH2OH
4-FC6H4CH2OH
3-FC6H4CH2OH
4-ClC6H4CH2OH
2-ClC6H4CH2OH
4-BrC6H4CH2OH
4-CF3C6H4CH2OH
4-NO2C6H4CH2OH
CH3CH2CH2CH2OH
84
Trace
Trace
44
Trace
n.d.
55
73
85
63
62
9
9
10
11
12
13
14
15
16
17c
18d
10
11
12c
13c
14
KOH (1.0)
KOH (1.0)
KOH (1.0)
76
56
43
a Reaction conditions: 1a (0.50 mmol) and 2a (0.25 mmol) in 1 mL of
H2O, Au/DNA (Au: 3.8 mol%), KOH (1.0 equiv), 50 °C, O2 balloon, 12 h.
b Isolated yield. c 80 °C.
a Reaction conditions: 1a (0.50 mmol) and 2a (0.25 mmol) in 1 mL of
H2O, Au/DNA (Au: 3.8 mol%), O2 balloon, 12 h. b Isolated yield. n.d. =
not detected. c Air. d N2.
showed high catalytic activity in this reaction. After compre-
hensive optimization, the standard reaction conditions were
established as below: Au/DNA as the catalyst, KOH as the base,
2 : 1 of 1a/2a as the molar ratio and the reaction being
conducted at 50 °C with an oxygen balloon.
Table 2 Synthesis of amides catalyzed by various catalystsa
With the standard conditions in hand, the scope of the
alcohols was extended (Table 3). The electronic effect
introduced by aromatic substitution of the alcohols had little
influence on the reaction. The reaction could tolerate both
electron-donating groups (entries 2–6) and electron-withdraw-
ing groups (entries 7–11). However, steric bulk had a negative
influence on this reaction. For instance, ortho substitution
strongly disfavored this reaction (entries 6, 10). These results
showed that the yields were dependent on the substituent’s
position on the phenyl ring in the order para- > meta- > ortho-
with identical substituent groups (entries 4–6). It was noted
that an alcohol bearing a strong electron-withdrawing group
(nitro or trifluoromethyl) could also be employed as the reac-
tion substrate at 80 °C to afford the corresponding product
with a good yield (entries 12 and 13). In particular, the
aliphatic n-butyl alcohol was also a good substrate.
Entry
Catalyst
Yieldb (%)
1
2
3
4
5
6
7
8
Au/DNA
Ag/DNA
Pd/DNA
Pt/DNA
Au/PVP
Au/TiO2
Au/CeO2
Au/PEG
None
85
n.d.
Trace
Trace
22
47
31
34
9
10
11
n.d.
n.d.
n.d.
DNA
KAuCl4
a Reaction conditions: 1a (0.50 mmol) and 2a (0.25 mmol) in 1 mL of
H2O, catalyst (metal: 3.8 mol%), KOH (1.0 equiv), 50 °C, O2 balloon,
12 h. b Isolated yield. n.d. = not detected.
Subsequently, the scope of the azides was examined. As
shown in Table 4, aromatic azides bearing electron-donating
groups (entries 1, 2) and electron-withdrawing substituents
(entries 3–5) could both proceed smoothly to give the desired
products in good yields. More importantly, benzyl azide was
successfully employed to afford the desired product in good
yield (entry 6). When the reaction temperature was elevated to
80 °C, benzyl azides bearing different substituted groups were
also good substrates to afford the corresponding products with
good yields (entries 7–10).
Ag/DNA, Pt/DNA and Pd/DNA, were synthesized and employed
in the reaction. However, the reaction hardly occurred using
these catalysts (entries 2–4). When Au/PVP, Au/PEG, Au/TiO2 or
Au/CeO2 was used, the desired product was obtained with only
a low yield (22–34%) (entries 5–8). When we employed DNA or
KAuCl4 as the catalyst, no desired product was observed
(entries 10 and 11). After the catalyst screening, only Au/DNA
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Table 4 Synthesis of amides from various azides and benzyl alcohola
Entry
R2–N3
Product
Yieldb (%)
1
2
3
4
5
6
4-MeOC6H4N3
4-MeC6H4N3
4-FC6H4N3
4-ClC6H4N3
4-BrC6H4N3
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ai
78
76
63
72
75
68
73
76
61
71
PhCH2N3
7c
8c
9c
10c
4-MeC6H4CH2N3
4-MeOC6H4CH2N3
4-FC6H4CH2N3
4-ClC6H4CH2N3
3aj
3ak
a Reaction conditions: 1a (0.50 mmol) and 2a (0.25 mmol) in 1 mL of
H2O, Au/DNA (Au: 3.8 mol%), KOH (1.0 equiv), 50 °C, O2 balloon, 12 h.
b Isolated yield. c 80 °C.
Table 5 The recycling of Au/DNA for the direct synthesis of amidesa
Scheme 2 Control experiments for the reaction mechanism.
Run
1
2
3
4
5
Yieldb (%)
85
83
82
79
77
a Reaction conditions: 1a (0.50 mmol) and 2a (0.25 mmol) in 1 mL of
H2O, Au/DNA (Au: 3.8 mol%), KOH (1.0 equiv), 50 °C, O2 balloon, 12 h.
b Isolated yield.
On the other hand, this Au/DNA catalyst was stable in air
with good reversible solubility in a mixture of water and
ethanol. By virtue of this characteristic, the catalyst could be
recovered by a simple phase separation. The recovered catalyst
could then be reused in the next round. As shown in Table 5, a
slight loss of catalytic activity was observed after the fifth
round, giving the corresponding amide with a yield of 77%.
The TEM image of Au/DNA after the fifth round showed that
the gold nanoparticles had aggregated a little (see Fig. S2 in
the ESI†). A little leaching of the gold nanoparticles was also
detected (see ICP analysis in the ESI†).
To gain an insight into the mechanism for the synthesis of
amides, several control experiments were performed under
standard conditions (Scheme 2). Firstly, a hydrogen transfer
reaction was performed using azidobenzene and 1-phenyletha-
nol, affording the corresponding amine in 42% yield
(Scheme 2a). When toluene or methanol was used as the
solvent instead of water, however, no amide product was
obtained, which showed that water was crucial for this reaction
(Scheme 2b). Moreover, when water was employed as the
solvent, the oxidative coupling reaction of aniline with benz-
Scheme 3 The proposed mechanism for the reaction.
aldehyde gave the amide product in 91% yield, which revealed
that aniline and benzaldehyde were the intermediates. When
toluene was employed as the solvent, the reaction could not
take place (Scheme 2c). Unexpectedly, azidobenzene could
react directly with benzaldehyde to afford the corresponding
amide in 47% yield and we could detect some benzoic acid
after this reaction (Scheme 2d). However, no amide product
was obtained when benzoic acid and aniline were used as the
substrates (Scheme 2e).
In terms of these experimental results and previous
reports,3c,14c,15 the possible mechanism is depicted in
Scheme 3. First of all, the azide is reduced to the amine by
hydrogen which is liberated from the alcohol through a hydro-
gen transfer process under the catalysis of Au/DNA. Then the
generated amine and aldehyde could afford the corresponding
amide through oxidative condensation, which is the first
pathway and also the main pathway. The other pathway
involves water attacking the aldehyde to generate the diol,
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1
which can react with another azide to give the amine and the gel. The resulting products were characterized by H NMR and
carboxylic acid by-product. The obtained amine can then give 13C NMR.
the amide product, similar to in the first pathway. In short, the
azide is used as the nitrogen source twice through two hydro-
gen transfer and two oxidative coupling processes to afford the
amide product in this catalytic cycle.
Acknowledgements
In conclusion, an efficient synthesis of amides from azides We are grateful to the National Nature Science Foundation of
and alcohols was developed. To the best of our knowledge, China (2127222, 91213303, 21172205, J1030412).
this is the first example of this tandem reaction catalyzed by
gold nanoparticles. In this catalytic system, a hydrogen trans-
fer process and an oxidative coupling process could synergisti-
cally take place to afford the required product. Taking
Notes and references
advantage of the water-soluble reversibility of the catalyst,
all of the transformations proceed well in water under mild
conditions and the catalyst can be recovered and reused by a
simple phase separation. A detailed mechanism and other
applications of the catalyst in organic reactions are in
progress.
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solved in 10 mL Tris buffer (10 mM, pH = 7.4). The combined
solution was stirred for 24 h to ensure the Au3+ were
thoroughly bound to the DNA. After this aging process,
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General procedure for the synthesis of amides from alcohols
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