Water dispersed gold nanoparticles catalyzed aerobic oxidative cross-dehydrogenative coupling: An efficient synthesis of α-ketoamides in water

Article abstract of DOI:10.1016/j.tetlet.2018.08.042

An effective green synthesis of α-ketoamides was developed for the first time in water via gold nanoparticles (AuNPs) catalyzed aerobic oxidative cross-dehydrogenative coupling of secondary amines with phenylglyoxals with a broad substrate scope.

Full text of DOI:10.1016/j.tetlet.2018.08.042

Accepted Manuscript
Water Dispersed Gold Nanoparticles Catalyzed Aerobic Oxidative Cross-De-
hydrogenative Coupling: An Efficient Synthesis of α-Ketoamides in Water
Narasimha Swamy Thirukovela, Ramesh Balaboina, Ravinder Vadde, Chandra
Sekhar Vasam
PII:
S0040-4039(18)31043-8
https://doi.org/10.1016/j.tetlet.2018.08.042
TETL 50217
DOI:
Reference:
To appear in:
Tetrahedron Letters
Received Date:
Revised Date:
Accepted Date:
14 July 2018
17 August 2018
21 August 2018
Please cite this article as: Thirukovela, N.S., Balaboina, R., Vadde, R., Sekhar Vasam, C., Water Dispersed Gold
Nanoparticles Catalyzed Aerobic Oxidative Cross-Dehydrogenative Coupling: An Efficient Synthesis of α-
Ketoamides in Water, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.08.042
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Graphical Abstract
Water Dispersed Gold Nanoparticles
Catalyzed Aerobic Oxidative Cross-
Dehydrogenative Coupling: An Efficient
Leave this area blank for abstract info.
Synthesis of α-Ketoamides in Water
a
a
Narasimha Swamy Thirukovela , Ramesh Balaboina ,
a
,
b
Ravinder Vadde * Chandra Sekhar Vasam *

1
Tetrahedron Letters
journal homepage: www.els evier.com
Water Dispersed Gold Nanoparticles Catalyzed Aerobic Oxidative Cross-
Dehydrogenative Coupling: An Efficient Synthesis of α-Ketoamides in Water
a
Narasimha Swamy Thirukovela, Ramesh Balaboina, Ravinder Vadde,* Chandra Sekhar Vasam,*
a
a
b
aDepartment of Chemistry, Kakatiya University, Warangal, Telangana State-506009, India, Tel :+91-9533945588, Email:
b
ravichemkuc@gmail.com; Department of Pharmaceutical Chemistry, Telangana University, Nizamabad, Telangana State, India
;
E-mail: csvasamsa@gmail.com
ARTICLE INFO
ABSTRACT
Article history:
Received
An effective green synthesis of α-ketoamides was developed for the first
time in water via gold nanoparticles (AuNPs) catalyzed aerobic oxidative
cross-dehydrogenative coupling of secondary amines with phenylglyoxals
with a broad substrate scope.
Received in revised form
Accepted
Available online
Keywords:
α-Ketoamides
Aerobic oxidative CDC
Recyclable water dispersed AuNPs
Phenylglyoxals
2
009 Elsevier Ltd. All rights reserved.
Homogeneous catalysis
α-Ketoamides and their derivatives are valuable
synthesis of α-ketoamides are : (i) use of toxic organic
solvents (ii) use of excess of secondary amines to
17 15
couple with phenylglyoxal and (iii) use of additives.
1
-8
building blocks in natural products, drug research and
15-17
9
-12
organic synthesis. Hence, the optimal synthesis of α-
ketoamides via both classical and catalytic methods has
been receiving considerable attention. In classical
methods, the condensation reaction between α-ketoacid
derivatives with amines is generally used to obtain α-
Since the α-ketoamides are naturally occurring
molecules, the use of water stable catalytic system in the
oxidative CDC reaction to synthesize α-ketoamides
would be more environmentally benign and highly
1
3
ketoamide. However, in recent years considerable
1
9
desirable objective for sustainable organic synthesis.
In line of the proposal, the use of coinage metal catalysts
Cu, Ag, Au) appears to be good choice in aqueous
efforts have been made towards catalyzed synthesis of
1
4
α-ketoamides to implement green chemistry principles.
(
phase oxidative CDC because of their (i) high degree of
tolerance toward air and moisture, (ii) relative lower
toxicity than many of the other d-block metal catalysts
and (iii) switchable stable oxidation numbers during
catalytic cycle. Besides, metalophilic attractions
between coinage metal centers also contribute to their
catalytic activity as reported previously.
In literature, there are three aerobic oxidative cross-
dehydrogenative coupling (CDC) of amines and α-
carbonyl aldehydes via homogeneous/heterogeneous
catalysis have been reported (Scheme 1A-1C) to
1
5-17
synthesize α-ketoamides.
oxidative CDC reactions are one of the referred methods
In general, aerobic
1
8
to construct C-C and C-X bonds. Nevertheless, the
probable disadvantages of reported catalytic aerobic
oxidative CDCs those would limit the sustainable

2
Tetrahedron Letters
Cu(I) and Ag(I) salts were introduced as catalysts in the
same oxidative CDC (Table 1, entries 2-6). It was
noticed that the intended oxidative CDC was occurred
and produced the desired α-ketoamide product 3a as
yellow oil. Later, the product 3a was separated by
extraction procedure using ethyl acetate. However, the
yields of 3a were found to be very low in the range of
1
2-29% (Table 1, entries 2-6). In order to improve the
yield of 3a in water, we next investigated the efficiency
of Au(I) and Au(III) salts in the above oxidative CDC
reaction (Table 1, entries 7-9). As shown table 1, this
time a moderate yield (69%) of product 3a was obtained
Scheme 1. (A), (B) and (C) are previous aerobic
15-17]
in the presence of NaAuCl
4
as catalyst (Table 1, entry
provided
[
oxidative CDC approaches;
(D) This work.
9
). On the other hand Au(I)Cl and Au(III)Br
3
As shown in scheme (1A-1C), previously the
the yields of 3a in 44% and 51% respectively (Table 1,
oxidative CDC of phenylglyoxals with secondary
amines was investigated in organic solvents using
entry 7-8).
1
5
16
homogeneous Cu(I) & Au(III) ion catalysts and
Table 1. Optimization of the reaction conditions
1
7
heterogeneous Cu-MOF catalysts. Since the majority
of known α-ketoamide products of this reaction are oils
or gummy solids, we thought that it would be better to
investigate the above CDC reaction in water/aqueous
phase using homogeneous and heterogeneous coinage
metal catalysts. At this juncture, we were intended to
explore the catalytic potential of water dispersed gold
nanoparticles (AuNPs) in the above CDC reaction to
optimize the synthesis of α-ketoamides. It is interesting
to note that previously variety of AuNPs including
water-dispersed AuNPs were used in oxidative amide
bond synthesis by alcohol-amine or aldehyde-amine
o
Entry Catalyst(mol%) Temp( C) Time (h)
Yield(%)
NR
12
1
2
3
4
5
6
7
8
9
-
CuBr (3)
2
60
60
60
60
60
60
60
60
60
24
12
12
Cu(OTf) (3)
14
12
12
Ag
2
O (3)
(3)
18
AgBF
4
21
12
Ag(OTf) (3)
AuCl (3)
29
2
0
coupling. The concept of AuNPs catalyzed amide
synthesis via oxidative coupling also suits well to design
AuNPs catalyzed ketoamide bond synthesis via
oxidative CDC between α-ketoaldehydes and amines.
6
44
AuBr
Na.AuCl
3)
AuNPs (1)
3
(3)
6
5
51
4
.2H
2
O
69
(
Herein we present the results of water-dispersed
AuNPs (5 nm) catalyzed aerobic oxidative CDC
coupling reaction between α-ketoaldehydes and
secondary amines in the high yield synthesis of a range
of α-ketoamides.
1
0
1
2
3
4
5
60
60
60
RT
50
60
1.5
2.5
1.5
12
85
79
1
1
1
1
1
AuNPs (0.5)
AuNPs (1.5)
AuNPs (1)
AuNPs (1)
AuNPs (1)
85
47
4
69
Initially, we have investigated the aerobic oxidative
CDC of phenylglyoxal monohydrate (1a) and
morpholine (2a) under open air conditions in water
medium as a model reaction using different coinage
metal salts (Cu(I), Ag(I), Au(I) and Au(III)) as catalysts
to optimize the reaction conditions. The details of the
reaction conditions and the outcome of the reaction were
depicted in table 1. It was observed that there was no
oxidative CDC reaction between the substrates 1a and
1.5
NRc
a
c
Unless otherwise stated, reaction was carried out with Phenylglyoxal
monohydrate (1.0 mmol) and morpholine (1.1 mmol) in 5 mL of water
b
under open air. Isolated yields after coloumn chromatography.
2
Reactions was carried out under N atmosphere. NR = no reaction.
At this juncture, we were intended to explore the
catalytic efficiency of water dispersed gold
nanoparticles (AuNPs) by considering their special
surface properties than the bulk gold. AuNPs can
activate effectively the areal oxygen-Au surface binding,
2
a in the absence of a catalyst (Table 1, entry 1). Next,

3
which indeed is essential step to initiate the oxidative
coupling reaction. We thought that this step would be
further useful to design AuNPs catalyzed oxidative CDC
reactions. In this circumstance, 85% of (3a) was
obtained from oxidative CDC between 1a and 2a in the
presence 1 mol% water dispersed PEG-stabilized
(ortho-, meta-, and para-position) of phenylglyoxal
derivatives were smoothly converted into the desired
products in good yields (3e-3w). The phenylglyoxals
those bearing electron-withdrawing groups (3k-3u, 3w)
were found suitable to give slightly higher yield of
corresponding product than phenylglyoxal derivatives
bearing electron-donating group (3e-3j, 3v). Later the
substrate scope extended to use a variety of secondary
amines. All the aliphatic secondary amines worked well
in the oxidative CDC reaction and afforded the desired
products in moderate to good yields. Among them, the
reactions using pyrrolidine produced higher yields of
corresponding α-ketoamides as compared to the other
amines (3c, 3f, 3m, 3q, 3r and 3t). Acyclic amine such
as diethylamine was also found to be appropriate for the
oxidative CDC reaction to afford yields in 66%-73%
range (3d-3e, 3j, 3p and 3s). All the synthesized
o
AuNPs as catalyst at 60 C within 1.5 hour only (Table
1
, entry 10). The synthesis of PEG-stabilized AuNPs
2
1
(
~5 nm) dispersed in water
is described in
experimental (see ESI for details). Further we have also
examined the effect of concentration of AuNPs and
effect of temperature on above oxidative CDC (Table 1,
entries 11-14). However, the activity of 1 mol% of
o
AuNPs at 60 C was found to best to optimize the
synthesis of 3a. It is also interesting note that, under N
2
inert atmosphere conditions (in the absence of air) only
the hemi-aminal was observed, but there was no
indication of forming the product 3a (Table 1, entry 15).
This finding indicates the role of areal oxygen in the
oxidative CDC between α-ketoaldehydes and amines to
form α-ketoamides.
1
13
products were characterized by H NMR, C NMR and
mass spectrometry and the details are given in ESI.
On the basis of the above results (Table 1, entry 1
&
15), and from the literature support, we proposed a
plausible mechanism as shown in Scheme 3. Initially,
iminium (A) was formed by the condensation of
phenylglyoxal and secondary amine. Later water was
Table 2.Substrate scope
2
2
added to iminium ion to form hemi-aminal (B). Now
the hemi-aminal was activated by oxygen
adsorbed/bound AuNPs (C) and forms surface activated
AuOOH-hemiaminal intermediate (D) via dehydration
process. This is because of the role of adsorbed oxygen
or OH in facilitating β-H elimination on gold as
2
3
suggested by a recent report, which demonstrates the
thermodynamic favorability of direct H-transfer to
adsorbed O
hand, it is also possible that in the presence of excess of
on gold, all the liberated H immediately converts to
water due to the high activation barrier for
2
or OH, forming OH or water. On the other
O
2
2
2
4
recombinative desorption of H on Au. Finally the β-H
2
elimination of activated hemiaminal intermediate (D)
could facilitate the formation of desired α-ketoamide
product by removing water.
a
1 13
All products were characterized by H and C NMR spectroscopy.
b
Isolated yields after column chromatography.
With the optimized reaction conditions in hand, we
further observed the scope of different phenylglyoxal
derivatives and secondary amines. The results are
summarized in table 2. It is found that the both electron
deficient and electron-rich groups at different position
Scheme 3. A plausible reaction mechanism

4
Tetrahedron Letters
The reusability of the water dispersed AuNPs were
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The authors are thankful to the UGC-New Delhi (F.No:
1
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5/2011 Indo-South Africa project) for financial
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7
The results of this work are comparable are
relatively better than the previous works.
2
The crucial role of areal O to initiate the oxidative
CDC was also noticed with the help of controlled
experiments.
At the end, we have also described the recyclability
of above water dispersed Au nanoparticle catalytic
system.