Graphene oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under neat conditions

Article abstract of DOI:10.1016/j.tetlet.2019.151470

Graphene oxide (GO) in conjunction with tetra n-butyl ammonium bromide (TBAB) was found to function as an efficient catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones in a single reaction vessel. Benzaldehydes and acetophenone were coupled in situ to produce their corresponding chalcones which underwent a subsequent aza-Michael addition under solvent-free condition. This procedure avoids the use of precious metals and the heterogeneous nature of the GO simplifies purification and isolation of the products by simple filtration of the catalyst.

Full text of DOI:10.1016/j.tetlet.2019.151470

Journal Pre-proofs
Graphene Oxide as a catalyst for one-pot sequential aldol coupling/aza-Michael
addition of amines to chalcones through in situ generation of Michael acceptors
under neat conditions
Dariush Khalili, Salime Lavian, Mohammadesmaeil Moayyed
PII:
S0040-4039(19)31269-9
DOI:
https://doi.org/10.1016/j.tetlet.2019.151470
TETL 151470
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
7 September 2019
23 November 2019
29 November 2019
Please cite this article as: Khalili, D., Lavian, S., Moayyed, M., Graphene Oxide as a catalyst for one-pot sequential
aldol coupling/aza-Michael addition of amines to chalcones through in situ generation of Michael acceptors under
neat conditions, Tetrahedron Letters (2019), doi: https://doi.org/10.1016/j.tetlet.2019.151470
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© 2019 Published by Elsevier Ltd.

Graphene Oxide as a catalyst for one-pot sequential aldol
coupling/aza-Michael addition of amines to chalcones
through in situ generation of Michael acceptors under neat
conditions
Dariush Khalili, *a Salime Laviana and Mohammadesmaeil Moayyeda
Department of Chemistry, College of Sciences, Shiraz University, Shiraz 71467-13565, Iran.
E-mail: khalili@shirazu.ac.ir
Abstract
Graphene oxide (GO) in conjunction with tetra n-butyl ammonium bromide (TBAB) was found to function
as an efficient catalyst for one-pot sequential aldol coupling/aza-Michael addition of amines to chalcones
in a single reaction vessel. Benzaldehydes and acetophenone were coupled in situ to produce their
corresponding chalcones which underwent a subsequent aza-Michael addition under solvent-free
condition. This procedure avoids the use of precious metals and the heterogeneous nature of the GO
simplifies purification and isolation of the products by simple filtration of the catalyst.
Keywords: aza-Michael addition, chalcones, graphene oxide, solvent-free
Both academic and industrial chemistry are currently seeking new practical methods which
facilitate the construction of the C-N bond mainly due to the high prevalence of nitrogen-
containing compounds in pharmaceuticals and natural products.1 The conjugate addition of
nitrogen-based nucleophiles to α,β-unsaturated olefins which is termed as aza-Michael reaction,
is one of the most effective synthetic tools for constructing a new C-N bond.2 In this regard, β-
aminocarbonyl compounds, as a major product of aza-Michael reaction, have received great
attention from the scientific community due to their promising properties and applications.3-7 To
date, much efforts have been put forth for introducing efficient strategies for the synthesis of β-
aminocarbonyl compounds.8-14 Among various Michael acceptors, chalcones as biologically
active scaffolds 15, have been widely used in organic synthesis to establish Michael adducts.
However, synthesis of chalcones, as a key component in aza-Michael reaction, has still
remained a great challenge because their formation needs to be carried out under strongly

acidic or basic conditions.15 Moreover, the addition of nitrogen-based nucleophiles to chalcones
also has some drawbacks such as the use of toxic solvents and metals, poor compatibility with
various substrate functional groups and polymerization of labile enones in acidic/basic
conditions.10, 16, 17 To remove these obstacles, the use of heterogeneous catalytic systems
appears to be a valuable solution and carbon materials with superior physicochemical properties
18, 19
can be good nominee for this goal. Graphene oxide (GO)20, 21 as an oxide-functionalized
derivative of graphene, is particularly promising due to the high biocompatibility and it’s rich
23
surface chemistry and acidic nature.22,
Recently, in a pioneering effort, Bielawski et al.
reported a metal-free, GO-mediated, formation of chalcones in an auto-tandem fashion.24
Inspired by this report and our ongoing interests in GO-catalyzed organic reactions 25-27 we tried
the GO-catalyzed sequential aldol coupling/aza-Michael addition of amines to chalcones that
generated in situ from acetophenones and benzaldehydes under solvent and metal-free
conditions. The success of GO as a much greener carbocatalyst attributes to the advantages of
its rich surface chemistry and its capacity to perform organic transformations in a metal-free
environment, under mild reaction conditions. In this strategy, the sequential reactions also occur
without separation of Michael acceptors as intermediates and a broad range of aromatic amines
can be converted to the desired β-amino ketones in isolated yields of up to >94%. In fact, the
present catalytic system is based on in situ production of chalcones which are commonly
considered as less active substrates than other Michael acceptors in such transformations.
Literature methods available for the successful addition of arylamines to electron-deficient
alkenes are not simple; Michael acceptor should contain a very active double bond such as
ethenetricarboxylates28 and nitroalkenes,29 and specific reaction conditions such as highly polar
protic solvents,30 basic ionic liquids31 and surfactants32 are required. Even in these conditions,
the efficiency of nucleophilic addition of aryl amines is not acceptable. By considering these
facts, the possibility of using of aromatic amines which are weak nucleophiles in aza-Michael
addition, is another attractive feature of our method.
O
H
Ar
Ar
O
NH
O
Carbon-based catalyst, ArNH2
aza-Michael addition
Carbon-based catalyst
Coupling reaction
+
Ar
Ar
Ar
Ar
O
H3C
Ar

Graphite oxide was synthesized from natural flake graphite (particle size: <50μm, from Merck)
by a modified Hummers method.33 The prepared graphite oxide was dialyzed in a dialysis bag
for 48 h to ensure the complete removal of salts, residual acids and metallic impurities. Then the
graphite oxide aqueous suspension was ultrasonicated for at least 1 h to form graphene oxide
(GO). The as-synthesized GO was characterized completely by using various analytical
techniques such as Raman, IR, XRD, UV-Vis and TGA techniques to establish its authenticity.
To determine the amounts of -COOH and -OH groups, a solid-based titrimetry method was
used.34 Based on the titration curves the amounts of -COOH and -OH were evaluated to be 0.71
and 1.13 mmol/g, respectively. The initial pH value of GO was 4.4, at approximately 0.1 mg mL-
1, which is consistent with previous reports.35
Initially, the reaction between benzaldehyde 1a (1 mmol) and acetophenone 2a (1 mmol) was
chosen as a model reaction. As a mixture of 1a and 2a was stirred in refluxing H2O, the coupling
reaction was carried out in the presence of GO (80 mg) to produce the chalcone. Further
reaction of chalcone intermediate with aniline (1.1 mmol) in the same condition, generated the
final corresponding aza-Michael adduct 3a in very low yield (entry 1).
Table 1. Optimization of the reaction conditionsa
Ph
O
NH
O
O
H
1) Catalyst (mg), solvent, T °C
2) PhNH2, condition
H3C
+
3a
1a
2a
Entry
1
Catalyst (loading)
GO(80 mg)
GO(80 mg)
GO(80 mg)
GO(80 mg)
GO(80 mg)
GO(80 mg)
GO(80 mg)
GO(80 mg)
-
Solvent (condition)
H2O, reflux
Time (h)
24
Yield of 3ab
12
31
2
CH2Cl2, reflux
24
3
THF, reflux
24
45
4
EtOH, reflux
24
52
5
CH3CN, reflux
24
59
6
Solvent-free, 100 ºC
Solvent-free, 100 ºC
Solvent-free, 100 ºC
Solvent-free, 100 ºC
Solvent-free, 80 ºC
Solvent-free, 110 ºC
Solvent-free, 100 ºC
Solvent-free, 100 ºC
16
72
7c,d
8e
16
84
16
74
9f
48
trace
66
10c
11c
12c
13c
GO(80 mg)
GO(80 mg)
GO(70 mg)
GO(100 mg)
24
16
84
16
74
16
87

14c
15c
16c
Graphite(80 mg)
activated carbon (80 mg)
r-GO (80 mg)
Solvent-free, 100 ºC
Solvent-free, 100 ºC
Solvent-free, 100 ºC
16
16
16
trace
30
38
aThe reactions were performed with benzaldehyde (1 mmol), acetophenone (1 mmol), aniline (1.1
b
c
mmol) and a carbon catalyst (type indicated). Isolated yield. TBAB (30 mol%) was used as an
additive. dBold values reflect the best optimized condition. eReaction was performed in the presence of
20 mol% of TBAB. fBlank experiment without graphene oxide.
When other solvents such as CH2Cl2, THF, EtOH and CH3CN were applied instead of H2O
(entries 2-5), maximum yield of 59% was obtained in 24 h. When the model reaction was
performed under solvent-free condition at 100 °C, aza-Michael addition proceeded smoothly
and the product 1,3-diphenyl-3-(N-phenylamino)-1-propanone (3a) was obtained in 72% yield
within 16 h (entry 6). To our delight, when the above reaction carried out using tetra n-butyl
ammonium bromide (TBAB, 30 mol%) as an additive at 100°C, the reaction was completed
within 16 h and 3a was obtained in 84% yield (entry 7). The same reaction was repeated using
lower loading of TBAB (20 mol%) and the product 3a was obtained in 74% yield after 16 h
(Table 1, entry 8). Other quaternary ammonium salts such as TBAC and TBAI were also tested.
The studies showed that TBAB and TBAC were nearly equally efficient additives for sequential
aldol coupling/aza-Michael addition reaction while TBAI was found to be less effective in the
model reaction. This can be justified by considering their melting points (TBAC: 41-44 °C;
TBAB: 100-102 °C; TBAI: 143-146 °C) and the reaction temperature (100 °C). However, since
the TBAB is more inexpensive than TBAC, this compound was chosen as the additive of choice
in this reaction. Using solvent-free conditions, approaching reactants which were soluble in
organic solvents and GO which was well-dispersible in H2O36 was an issue. To overcome this,
quaternary ammonium salts were used where the both reactants and the catalyst experienced
an efficient reaction medium to move toward each other with help of quaternary ammonium
salts. So, its positive effect might be explained from the fact that TBAB can facilitate the
approach of substrates to the GO surface24 and easier formation of intermediates.37 The model
reaction without GO gave trace amounts of product 3a even after 48 h which confirmed the
active role of the catalyst (entry 9). Lowering the reaction temperature to 80 °C decreased the
yield of 3a to 66% even with a prolonged reaction time (entry 10). Moreover, an increase in the
reaction temperature (110 °C) did not show any beneficial effect (entry 11). We next examined
the effect of the amount of catalyst on this sequential reaction. When the amount of the catalyst
was reduced to 70 mg, the yield of 3a decreased obviously while an increase in the amount of
GO (100 mg) led to no increment in the yield (entries 12 and 13). Under the same conditions,

the other carbon materials like natural flake graphite, activated carbon,38 hydrazine reduced
graphene oxide21 resulted in poorer yields (entries 14-16). After optimizing the conditions for
both coupling and aza-Michael addition reaction, the catalytic efficiency of GO was further
explored with aldehydes and anilines bearing electron donating and electron withdrawing
groups (Table 2).
Table 2. GO-catalyzed sequential aldol coupling/aza-Michael addition of amines to chalcones.a
O
Ar'
NH
O
O
1) GO, TBAB, solvent-free, 100 °C
2) Ar'NH2
H3C
+
Ar
Ar
H
1
2a
3a o
-
Entry
1
Aldehyde
Amine
β-amino ketones
Yield (%)b
NH
O
84
H2N
3a
3b
H3CO
H2N
OCH3
NH O
87
2
3
EtO
NH O
3c
3d
88
H2N
OEt
O
H
CH3
CH3
CH3
H3C
H2N
4
5
85
90
NH O
CH3
N
CH3
N
CH3
H3C
H2N
3e
3f
NH O
Et
N
Et
Et
N
Et
6
H2N
87
NH O

Br
H2N
NH O
7
8
3g
3h
74
59
Br
H2N
NH
O
H2N
H3CO
NH O
NH O
NH O
9
3i
3j
83
81
OCH3
H2N
H3C
10
CH3
11
12
H2N
3k
3l
88
90
O2N
H3CO
NH O
H2N
OCH3
O2N
EtO
O
NH O
13
14
15
3m
3n
3o
90
94
80
H2N
OEt
CH3
H
O2N
O2N
CH3
N
H3C
H2N
N
CH3
NH O
O2N
Cl
H2N
NH O
Cl
O2N

H3CO
OCH3
NH
H2N
H3CO
OCH3
O
16
3p
85
O2N
aReaction conditions: aldehyde (1 mmol), acetoophenone (1 mmol), anilines (1.1 mmol), GO (80 mg),
TBAB (30 mol%), under solvent-free condition at 100 °C. bIsolated yield.
It is worth mentioning that the presence of electron-withdrawing groups on aldehydes and
electron-donating groups on anilines resulted in better yields. Anilines with electron-donating
alkoxy and alkyl groups reacted well under these conditions to give the desired products 3b-d in
high yields. N,N-Dialkylbenzene-1,4-diamines (entries 5 and 6) also underwent sequential aldol
coupling/aza-Michael addition with benzaldehyde 1a and acetophenone 2a to give the
corresponding products 3e and 3f in 90 and 87% yields, respectively. As evident from the
results, the position of the substituents, had a significant role in the reactivity of the aniline. For
instance, when 2-bromoaniline was used to react with chalcone intermediate, only 74% of the
desired β-amino ketones was observed owing to their steric hindrance. The use of higher steric
hindrance aniline such as 2-isopropylaniline also led to low yield of the corresponding β-amino
ketone 3h (entry 8, 59%)
Anilines bearing electron-rich substituents (-OMe, -Me) on their meta-positions also gave the
desired products 3i-j in high yields. It is worth mentioning that in the first step, replacement of
benzaldehyde with 4-nitrobenzaldehyde led to the incremental improvements of the yield of
chalcone formation. As expected, this improvement in chalcone formation, positively affected
the final production of β-amino ketones (Table 2, entries 11-16). To study the role of the
carboxylic acid groups of the GO catalyst, GO was treated with aqueous 0.1 N sodium
hydroxide under stirring for 12 h at room temperature. Fourier transform infrared (FTIR)
absorption spectroscopy was performed to analyze the functional groups in base-treated GO
(Figure 1). The FTIR spectrum of b-GO showed that the intensity of carboxyl band at 1720 cm-1
decreased, while the new peak originates from the carboxylate group increased in intensity.39, 40
This spectral information confirmed the presence of carboxylate groups after the base
treatment. When the model reaction was carried out using b-GO as a catalyst, it was found that
the presence of carboxylate groups substantially suppressed the catalytic activity of b-GO.
Finally, a control experiment was conducted to support the involvement of COOH groups of GO
in the catalytic reaction. For this purpose, 1-pyrene-carboxylic acid was used as a model
catalyst to mimic the graphene-based material. Gratifyingly, 1-pyrenecarboxylic acid resulted in

high yield of the catalytic model reaction while pyrene itself had no activity in the sequential
aldol coupling/aza-Michael addition of amines to chalcones. This finding proved the crucial role
of the π−π* backbone and acidic groups of GO in the catalytic action.40, 41
Figure 1. Normalized transmission infrared absorbance spectra of GO and b-GO
Furthermore, to determine whether metal impurities in GO were involved in this sequential
reaction, the as-prepared GO was analyzed by inductively coupled plasma atomic emission
spectroscopy (ICP-AES). The Mn content (used in the preparation of GO) was measured to be
less than 40 ppb via ICP-AES which is nearly equivalent to other trace metal contaminants
found in the material.22 The obtained results indicated that the metal impurities have no effect on
the catalytic activity of GO. The recyclability of GO was tested for sequential aldol coupling/aza-
Michael addition of benzaldehyde 1a, acetophenone 2a and aniline under optimized reaction
condition. The catalytic deactivation was observed after 6th cycle (Table 3).
Table 3: Reusability studya
Run
1
2
3
4
5
6
Yield of 3ab
84
84
83
82
82
80
aReaction conditions: benzaldehyde (1 mmol), acetoophenone (1 mmol), aniline (1.1 mmol), GO (80
mg), TBAB (30 mol%), under solvent-free condition at 100 °C. bIsolated yield.
It should be noted that during the recycling experiments, the GO catalyst was recovered from
the reaction mixture by simple filtration after previous runs, washed with warm ethanol several

times and dried in a vacuum before starting the next test. In order to evaluate the structure of
the GO after 6 runs, Raman spectroscopy was taken for spent catalyst (Figure 2). The obtained
Raman spectra of GO and recovered GO indicated the partial reduction of recovered GO after
the last run. The G band red-shifted from 1593 cm-1 in the GO spectrum to 1581 cm-1 in the
spectra for recovered GO while the ID/IG ratio increased from 0.97 for GO to 1.24 for recovered
GO. Both the red-shift of the G band and the increase in the intensity ratio (ID/IG) can be
attributed to the recovery of sp2 domains in the graphitic structure and is consistent with most
43
chemical reduction reports.42,
The spent GO was also characterized by X-ray diffraction
method. As can be seen from Figure 2, the peak intensity at 11.53° decreased and a new broad
peak with the maximum at 2θ = 26.46° appeared. The observation of characteristic d002
reflection of graphite at 26.46 indicated that the GO catalyst underwent partial reduction after 6th
run.
Figure 2. Raman (left) and XRD (right) spectra of GO and recovered GO after 6th run
Moreover, the as-prepared GO was measured to have a specific surface area of 23.3 m2g-1
using the BET method. The BET surface area of the recovered catalyst did not show obvious
differences compared with the starting material.
The plausible mechanism of this sequential aldol coupling/aza-Michael addition reaction is
illustrated in Fig. 3. GO as a Brönsted acid catalyst facilitates in situ chalcone formation from the
aldol product in an enol mechanism. Then chalcone I (which is activated via H-bond interaction
between the protons in acidic heterogeneous catalyst (GO) and the carbonyl group) reacts with
aniline to furnish intermediate II. Finally, a rapid tautomerization occurs to generate the aza-
Michael adduct III.

GO
O
GO
O
GO
O
H2NAr''
Ar'
H
NH2Ar"
Ar'
O
NHAr"
Ar'
O
O
1
H
Ar'
tautomerization
GO
GO
Ar
Ar
Ar
Ar
CH3
Ar
CH2
H2O
I
II
III
2a
Figure 3. A plausible mechanism
In summary, we demonstrated that GO in conjunction with tetra n-butyl ammonium bromide
(TBAB) was able to catalyze one-pot sequential aldol coupling/aza-Michael addition of aromatic
amines to chalcones in a single reaction vessel. The unique reactivity of GO facilitated access
to β-amino ketones from a wide range of commercially available starting materials, and in the
absence of metal catalysts. The obtained results showed that π−π* backbone and acidic groups
in the GO are responsible for its high catalytic efficiency. The catalyst had good recyclability
under solvent-free conditions without the formation of side products.
Acknowledgment
The authors are grateful to the Shiraz University for their financial support.
Conflict of interest
The authors declare no conflict of interest.
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Graphical abstract
O
H
O
Ar
Ar
NH
O
GO, TBAB, solvent-free, 100 °C
Coupling reaction
ArNH2
Ar
Ar
+
aza-Michael addition
Ar
Ar
O
H3C
Ar
Advantages:
 Metal- and solvent-free pathway
 Heterogeneous catalyst
 High yield of products
 Rapid recycling protocol
 Using a single reaction vessel

Highlights

GO catalyzed sequential aldol coupling/aza-Michael addition of aromatic amines to
chalcones




In situ generation of chalcones under solvent and metal-free conditions
Using of aromatic amines as weak nucleophiles in aza-Michael addition
Having easy and rapid recycling protocol for catalyst by filtration
Synthesis of β-amino ketones in high yields