Eco-friendly one-pot, three-component synthesis of novel derivatives of kojic acid by the Mannich-type reaction under solvent-free ball-milling conditions

Article abstract of DOI:10.1007/s11164-015-2221-0

A novel series of aminokojic acid derivatives were efficiently synthesized by one-pot condensation of kojic acid, aromatic aldehydes and heteroaromatic amines in the presence of cerium(III) sulphate as an efficient and recyclable catalyst in ball-milling

Full text of DOI:10.1007/s11164-015-2221-0

Res Chem Intermed
DOI 10.1007/s11164-015-2221-0
Eco-friendly one-pot, three-component synthesis
of novel derivatives of kojic acid by the Mannich-type
reaction under solvent-free ball-milling conditions
1
1
•
Reza Teimuri-Mofrad
Mahdi Gholamhosseini-Nazari
•
Aziz Shahrisa
1
1
•
Naser Arsalani
Received: 14 June 2015 / Accepted: 7 August 2015
Ó Springer Science+Business Media Dordrecht 2015
Abstract A novel series of aminokojic acid derivatives were efficiently synthesized
by one-pot condensation of kojic acid, aromatic aldehydes and heteroaromatic amines in
the presence of cerium(III) sulphate as an efficient and recyclable catalyst in ball-milling
under solvent-free conditions at room temperature. This synthesis method offers several
advantages, including a green and eco-friendly protocol, operational simplicity, mild
reaction conditions, short reaction time, higher yields and easy workup procedures. The
workup of these very clean reactions involves only a simple washing with acetone/cold
water. The catalytic system can be reused several times with no loss of activity.
Graphical Abstract
Ce2(SO4)3.5H2O
O
O
O
HO
O
O
HO
H
HO
Y
Y
N
N
N
Z
H
O
Y
N
N
Z
Z
X
X
H
2
N
N
Y
+
Z
X
or
X
O
H
R
O
O
N
H
HO
R
yields: 82-91%
X : OH, Cl
Y: H, CH
Z: CH, N
3
R: H, 2-Br, 3-Br, 3-NO
2
, 4-NO
2
, 4-Cl, 4-OMe, 4-Me, 4-CHO Room temperature
Solvent-free condition
Electronic supplementary material The online version of this article (doi:10.1007/s11164-015-2221-0)
contains supplementary material, which is available to authorized users.
&
Reza Teimuri-Mofrad
teymouri@tabrizu.ac.ir
1
Department of Organic and Biochemistry, Faculty of Chemistry, University of Tabriz,
Tabriz 5166614766, Iran
123

R. Teimuri-Mofrad et al.
Keywords Kojic acid Á Cerium(III) sulphate Á Ball-milling Á Solvent-free
Introduction
Kojic acid derivatives are an important class of natural and synthetic compounds
that have shown a wide range of biological activity, including anti-melanogenic [1],
tyrosinase inhibitory [2], antimicrobial [3], and anti-inflammatory activities [4],
whitening agents [5], antineoplastic [6], antifungal [7] and antibacterial activities
[
8], depigmenting agents [9], and anticonvulsant [10], antiviral [10] and anti-HIV
activities [11]. Therefore, the synthesis of kojic acid derivatives is of great
importance to organic chemists.
Multicomponent reactions (MCRs), in which multiple reactions are combined in
a one-pot synthetic operation, have been widely used in the preparation of bioactive
compounds [12, 13]. MCRs are highly significant in industrial, synthetic chemistry,
green chemistry and pharmaceutical chemistry applications for generation of
structural diversity and libraries of drug-like molecules [14]. Therefore, the
development of new MCRs and improvement of known MCRs for the synthesis of
novel compounds is an active areas of synthetic organic chemistry [15].
A number of synthetic approaches have recently been developed for the synthesis
of kojic acid derivatives using MCRs. Because of the phenol-like properties of kojic
acid, most of its MCRs involve the enolic moiety of this compound [16]. Three-
component reaction of kojic acid, aldehyde and 1,3-dione has been achieved to
afford dihydropyrano[3,2-b]chromenedione derivatives [17]. A series of novel
pyrano-[3, 2-b]pyrazolo[4,3-e]pyridin-8(1H)-ones were synthesized via three-com-
ponent condensation of kojic acid, 1-H-pyrazol-5-amines and aldehydes [18].
Three-component coupling of aldehyde, indole and kojic acid has been achieved
under solvent-free conditions to produce a novel series of 2-substituted aryl
(
indolyl)kojic acid derivatives with antifungal and antibacterial activities (Com-
pounds I, Fig. 1) [8]. Another MCR of kojic acid is the Mannich reaction. Because
of biological activates of Mannich bases, this reaction has attracted increased
interest (Compounds II, Fig. 1) [19–24]. However, a literature survey shows that
most reported articles of Mannich reactions concern the study of kojic acid,
O
O
HO
R
HO
C
N
R
H
C
N
O
O
H
2
OH
OH
I
II
NH
R= alkyl/ aryl
Fig. 1 Selected examples of bioactive kojic acid derivatives
R= alkyl/ alkyl/ H
1
23

Eco-friendly one-pot, three component synthesis of novel…
formaldehyde and secondary aliphatic amines. To the best of our knowledge, there
are no reports on three-component coupling of kojic acid, aromatic aldehydes and
heteroaromatic amines to produce a new class of kojic acid derivatives as novel
Mannich bases.
In recent years, the use of ball-milling (intense mechanical grinding) as an
efficient and green tool in organic synthesis has garnered great interest [25–32]. In
addition to numerous organic classical reactions, some MCRs have also been
performed using the ball-milling method [33, 34].
Lanthanide salts are useful as promoters and catalysts in organic synthesis [35,
6], and have attracted attention because of their ready availability, ease of handling
3
and low toxicity, as well as their air and water stability [37, 38]. Among them,
cerium salts have been widely applied in various organic synthetic reactions [39–
4
3]. Our findings indicate that cerium(III) sulphate is an efficient catalyst for our
synthesis and allows condensation reactions to occur under very mild conditions
with generally short reaction times and good yields. Moreover, its solubility
behavior in water, which increases in low temperatures, is helpful for both
purification and recycling purposes.
As part of our continued interest in the study of MCRs [44], we recently reported
an efficient method for the synthesis of a new class of Mannich base derivatives
[
45]. Herein we disclose a novel three-component reaction as a direct, efficient and
green method for the synthesis of aminokojic acid derivatives using Mannich-type
MCRs with cerium(III) sulphate as a recyclable catalyst under solvent-free ball-
milling conditions.
Results and discussion
Initially, the reaction of Kojic acid (1), 4-chlorobenzaldehyde (2) and 2-amino-6-
methylpyridine (3) was selected as a model reaction to investigate the feasibility of
the strategy and to optimize reaction conditions. A variety of catalysts were tested
for the model reaction in ethyl alcohol (C H OH) at room temperature (Table 1,
2
5
entries 1–13).
A comparison of catalytic activity among different Lewis acids and Lewis bases
showed the highest catalytic activity of Ce (SO ) Á5H O for producing the desired
2
4 3
2
aminokojic acid (Table 1, entry 4). It is also worth noting that the solubility of
cerium(III) in water increases at low temperatures, and this behavior was helpful for
us in the purification step. In the presence of Lewis bases, the condensation of kojic
acid and aldehyde was acquired, and only a trace amount of the desired product was
formed (Table 1, entries 11–13). Moreover, in the absence of the catalyst, the
product yield (4d) was very low, and an imine intermediate (B) was produced as the
main product (Table 1, entry 1).
For further optimization of reaction conditions, we tested acetonitrile, water and
ethanol/water mixtures as solvents (Table 1, entries 14–17), and found that the
desired product was obtained at a higher yield in C H OH 95 % (Table 1, entry 17).
2
5
In addition, in view of the benefits of solvent-free conditions, we attempted to
perform the model reaction under these conditions, but found that the reaction
123

R. Teimuri-Mofrad et al.
Table 1 Catalytic activity of various catalysts and optimization of conditions
O
O
O
HO
HO
HO
H
N
H
3
C
N
NH
O
2
H
3
C
N
HO
+
+
+
O
O
O
N
N
CH3
H
OH
OH
OH
3
b
1a
Cl
Cl
Cl
2
d
4d
A
B
Cl
Entry
Solvent
OH
Catalyst (mol%)
No catalyst
Time (h)
4d
A
B
1
2
3
4
5
6
7
8
9
C
C
C
C
C
C
C
C
C
C
C
C
C
2
2
2
2
2
2
2
2
2
2
2
2
2
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
H
5
20
14
14
14
14
14
14
14
14
14
14
14
14
14
14
14
14
2
Trace
39
42
61
53
54
51
52
44
41
–
Trace
21
50
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
La
CeCl
Ce (SO
CoCl
Á6H
Sb (5)
Bi(NO
Á5H
NiCl (5)
ZnCl
CuCl
2
O
3
Á(5)
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
Trace
3
(5)
17
2
4
)
3
Á5H
2
O (5)
10
2
2
OÁ(5)
18
2
O
3
11
3
)
3
2
O (5)
10
2
10
2
(5)
(5)
10
10
11
12
13
14
15
16
17
18
19
20
21
22
2
10
DABCO (5)
DBU (5)
70
–
53
Et
3
N (5)
–
41
CH
3
CN
Ce
2
Ce
2
Ce
2
Ce
2
Ce
2
Ce
2
Ce
2
Ce
2
Ce
2
(SO
(SO
(SO
(SO
(SO
(SO
(SO
(SO
(SO
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
4
)
3
3
3
3
3
3
3
3
3
Á5H
Á5H
Á5H
Á5H
Á5H
Á5H
Á5H
Á5H
Á5H
2
2
2
2
2
2
2
2
2
O (5)
O (5)
O (5)
O (5)
O (5)
O (5)
52
58
69
74
53
78
83
87
85
12
H
2
O
12
C
C
2
2
H
5
OH/H
2
O (90:10)
O (95:5)
Trace
Trace
10
H
5
OH/H
2
a
b
b
b
b
Solvent-free
Ball-milling
Ball-milling
Ball-milling
Ball-milling
0.5
0.5
0.5
0.5
Trace
Trace
Trace
Trace
O (7.5)
O (10)
O (12.5)
Reaction conditions: kojic acid/4-chlorobenzaldehyde/2-amino-6-methylpyridine = 1:1:1.1 at room
temperature
a
After 20 min, reaction mixture was solidified
b
Ball-milling carried out at 25 Hz
mixture was solidified, and the results showed that the reaction under these
conditions was not efficient (Table 1, entries 18).
When the reaction was carried out in ball-milling under solvent-free conditions,
the desired product (4d) was obtained at a higher yield (Table 1, entry 19). This
observation shows the importance of the highly efficient mixing of reagents under a
ball-milling process in comparison with convenient solvent-free conditions.
Furthermore, the model reaction was examined in the presence of different
quantities of Ce (SO ) Á5H O in ball-milling under solvent-free conditions
2
4 3
2
(
Table 1, entries 19–22). The best result (87 % yield) was obtained when the
1
23

Eco-friendly one-pot, three component synthesis of novel…
reaction was performed using 10 mol% of Ce (SO ) Á5H O in ball-milling under
2
4 3
2
solvent-free conditions at room temperature (Table 1, entry 21).
After optimization of the reaction conditions, in order to explore the scope and
generality of this procedure, condensation reactions of kojic acid derivatives with a
variety of aromatic aldehydes and heteroaromatic amines (Fig. 2) were examined in
the presence of Ce (SO ) Á5H O (10 mol%) in ball-milling under solvent-free
2
4 3
2
conditions.
As shown in Scheme 1, the reactions were carried out efficiently and the desired
products were produced in good to high yields. Aromatic aldehydes bearing either
electron-donating or electron-withdrawing groups reacted successfully and gave the
corresponding products in high yields.
The successful production of a series of arylaminokojic acid derivatives indicates
the generality of this method for such transformations. Based on these consider-
ations, we extended our multicomponent protocol to the synthesis of the bis-
arylaminokojic acid derivatives (5) in the presence of Ce (SO ) Á5H O (10 mol%)
2
4 3
2
in ball-milling under solvent-free conditions. The condensation of kojic acid with
bis-aldehyde (terephthaldehyde) and 2-amino-6-methylpyridine was successfully
performed and afforded two products 5a and 6 (Table 2).
When equimolar amounts of terephthaldehyde, kojic acid and 2-amino-6-
methylpyridine were reacted in the presence of Ce (SO ) Á5H O (10 mol%), bis-
2
4 3
2
arylaminokojic acid 5a and mono-arylaminokojic acid 6 were obtained at 19 and
4
5 % yields, respectively (Table 2, entry 1). However, the use terephthaldehyde
1 equiv.), kojic acid (2 equiv.) and 2-amino-6-methylpyridine (2 equiv.) in the
(
presence of Ce (SO ) Á5H O (10 mol%) afforded compounds 5a and 6 at 59 and
2
4 3
2
O
O
HO
HO
Kojic acides
Aldehydes
O
O
1
a
OH
1b Cl
Br
Br
Cl
O
O
O
O
O
O
O
O
O
H
2
a
H
2b
H
H
2c
H
H
2d
2e
H
O
NO2
Me
NO2
OMe
H
O
H
2f
H
2g
2h
2i
H
2j
N
H2N
N
Amines
H2N
N
CH3
H2N
N
3
a
3b
3
c
Fig. 2 Diversity of reactants used in the synthesis of aminokojic acid
123

R. Teimuri-Mofrad et al.
O
O
HO
HO
H
Z
+
Ar
H
+
Ball Milling
Ce2(SO4)3.5H2O
(10 mol%)
Y
N
N
O
Y
N
NH2
O
X
O
Z
Ar
X
1
a-c
2a-j
3a-c
4a-t
O
O
O
O
O
O
HO
HO
HO
HO
H
N
H
N
H
N
O
H
N
H3C
N
H3C
N
H3C
N
H3C
N
O
OH
Br
OH
OH
OH
4
a
4b
4c
4d
9
0%
89%
Br
91%
87%
2
5 min
25 min
25 min
30 min
Cl
O
O
O
O
O
O
HO
HO
HO
HO
H
N
H
N
H
N
O
H
N
H3C
N
H3C
N
H3C
N
H3
C
N
O
OH
OH
OH
OH
4
e
4f
4g
4h
8
3%
86%
30 min
O2N
90%
88%
3
5 min
25 min
30 min
OMe
NO2
O
O
O
O
O
O
O
O
HO
HO
HO
HO
H
N
H
N
H
N
H
N
N
N
N
N
OH
OH
OH
N
OH
4
i
4j
4k
4l
85%
30 min
8
5%
Br
91%
25 min
85%
3
0 min
30 min
Cl
Me
Scheme 1 Synthesis of compounds (4a–l) in ball-milling under solvent-free conditions
21 %, respectively (Table 2, entry 2). With improved reaction conditions to
terephthaldehyde (1 equiv.), kojic acid (2 equiv.) and 2-amino-6-methylpyridine
(
2.2 equiv.) in the presence of Ce (SO ) Á5H O (20 mol%), the corresponding bis-
2
4 3
2
arylaminokojic acid 5a was obtained at 87 % yield (Table 2, entry 5).
To explore the generality of this procedure for the synthesis of bis-arylaminoko-
jic acid derivatives, the reaction of kojic acid and amine derivatives with
terephthaldehyde was tested, and corresponding bis-products were afforded in
good yields (Scheme 2).
To the best of our knowledge, there is no report on the synthesis of
arylaminokojic acid derivatives through the MCR of kojic acid, aldehydes and
amines in the present of Ce (SO ) Á5H O (10 mol%) in ball-milling under solvent-
2
4 3
2
free conditions. Therefore, such synthesis can be considered as a powerful and
practical method for the preparation of a new class of kojic acid derivatives.
A plausible mechanistic rationalization of the cerium(III) sulphate-catalyzed
reaction is shown in Scheme 3. We assume that the Lewis acid–base interaction
between the catalyst and the oxygen of the aldehyde carbonyl group lead to an
electrophilic carbon atom. Continued condensation of amine with activated
aldehyde followed by dehydration generates an imine intermediate. Consequently,
the nucleophilic attack of the kojic acid to imine gives the desired product as
depicted in Scheme 3.
1
23

Eco-friendly one-pot, three component synthesis of novel…
Table 2 Optimization of amounts of catalyst and reactants for synthesis of bis-aminokojic acid
derivative
O
O
HO
HO
O
H
N
H
N
HO
+
H3C
H3C
N
N
H3C
N
O
O
OH
OH
OH
H2N
N
CH3
O
+
BallMilling
Ce2(SO4)3.5H2O
5
a
6
OH
3
b
1a
O
O
H
O
N
H
H
O
H
2
j
HO
O
Entry
Ce
2
(SO
4
)
3
2
Á5H O amount (mol%)
Aldehyde/kojic acid/amine (molar ratio)
Yield (%)
5
a
6
1
2
3
4
5
6
10
10
10
15
20
25
1/1/1
19
59
67
74
87
85
45
1/2/2
21
1/2/2.2
1/2/2.2
1/2/2.2
1/2/2.2
20
13
Trace
Trace
Ball-milling carried out at 25 Hz at room temperature for 30 min
Finally, the scale-up of this method was investigated and led to results similar to
those on a millimole scale. As the model, compound 4a was obtained within a few
1
minutes on a multi-gram scale using the established standard conditions. The H
NMR spectrum of the crude product was exactly the same as that obtained on a
millimole scale. Because the products could be isolated by washing with acetone
and cold water, the catalyst could be recovered and recycled by removing the water
under a vacuum. The results were the same for up to four successive catalytic
cycles, with no excessive loss of activity. As a result, the synthesis of compound 4s
could be achieved on a 7-gram scale with yields of 90, 87, 88 and 86 % for the
successive cycles.
Conclusions
In summary, we have demonstrated a simple and efficient route for the one-pot,
three-component synthesis of aminokojic acid derivatives using readily available
starting materials in ball-milling under solvent-free conditions at ambient temper-
atures. The significant features of this method are its short reaction times, high
product yields, operational simplicity, and easy workup procedure. In addition, the
catalyst can be recovered from large-scale experiments and easily recycled at least
four times without the loss of efficacy. New perspectives on the syntheses of bis-
and mono-arylaminokojic acid derivatives are envisaged, which could result in a
broad spectrum of applications in several fields of synthetic medicinal chemistry.
123

R. Teimuri-Mofrad et al.
Y
Y
N
O
N
Z
Z
HO
O
H
O
Z
NH
HN
Ball Milling
+
+
H
HO
OH
O
H
2
N
N
Y
Ce (SO ) 5H O
2
4
3.
2
X
(20 mol%)
O
O
O
O
1a,b
2j
3a-c
5a-e
X
X
CH
N
H C
3
CH
N
3
H C
3
3
N
N
NH
HN
NH
HN
OH
HO
OH
HO
5
a
5b
O
O
O
O
O
O
O
O
(
87%)
(84%)
3
0 min
30 min
OH HO
Cl
Cl
N
N
N
N
N
N
HN
NH
HN
NH
OH
HO
OH
HO
5
c
5d
O
O
O
O
O
O
O
O
(
82%)
5 min
OH HO
(83%)
3
35 min
OH HO
Scheme 2 Synthesis of bis-arylaminokojic acid derivatives (5a–d) in ball-milling under solvent-free
conditions
Experimental section
General methods
Melting points (mp) were determined using a MEL-TEMP model 1202D and are
uncorrected. FT-IR spectra were recorded on a Bruker Tensor 27 spectrometer as
1
KBr disks. The H NMR spectra were recorded with a Bruker-Spectrospin Avance
1
3
4
00 spectrometer with CDCl as solvent. C NMR spectra were determined on the
3
same instrument at 100 MHz. All chemical shifts were reported as d (ppm), and
coupling constants (J) are given in Hz. Elementary analyses (C, H, N) were
performed on a vario EL III analyzer. The ball-milling reactions were performed in
a Retsch MM 400 mixer mill with two stainless steel balls 10 mm in diameter in a
stainless steel jar (20 mL) at 25 Hz at room temperature. The chemical reagents
used in synthesis were purchased from Merck and Sigma-Aldrich and used without
further purification.
1
23

Eco-friendly one-pot, three component synthesis of novel…
δ–
Ce
2
(SO
R
4
)
3
δ
+
O
O
2 4
Ce (SO )
3
R
H
H
2 4
Ce (SO )
3
O
O
O
HO
R
H
2 4
Ce (SO )
3
H
Y
N
NH
2
2
- H O
2
Y
N
N
O
R
Y
N
N
X
Z
Z
Z
R
X : OH, Cl
Y: H, CH
Z: CH, N
3
R: H, 2-Br, 3-Br, 3-NO , 4-NO , 4-Cl, 4-OMe, 4-Me
2
2
O
O
O
O
HO
O
HO
H
N
H
N
H
H
Y
N
Y
N
Y
N
N
H shift
O
O
Z
X
Z
X
Z
X
R
R
R
Scheme 3 Proposed mechanism for the synthesis of the library of compounds (4a–l)
General procedure for the synthesis of aminokojic acid derivatives 4a–t
millimole scale)
(
A mixture of aldehyde (1 mmol), kojic acid (1 mmol), and amine (1.1 mmol) and
Ce (SO ) (10 mol%) was poured into a stainless steel double-walled ball-mill
2
4 3
beaker at room temperature for the appropriate time according to Scheme 1. After
completion of the reaction, as indicated by thin-layer chromatography (TLC)
(acetone–n-hexane, 2:1), the reaction mixture was washed with acetone (2 9 5 mL)
to remove unreacted materials and with cold water (2 9 10 mL) to remove the
catalyst. Finally, the solid product was dried to obtain the pure product. The isolated
1
13
compounds were characterized by mp, IR, H NMR, C NMR, and elemental
analysis (C, H, and N).
3
4
3
-Hydroxy-6-(hydroxymethyl)-2-[(6-methylpyridin-2-ylamino) (phenyl)methyl]-
H-pyran-4-one (4a) White solid; Yield 90 %; mp: 155–157 °C; FT-IR (KBr) m
438, 3266, 3068, 2848, 1650, 1606, 1575, 1217 cm ; H NMR (400 MHz,
-
1
1
DMSO-d ): d 2.22 (3H, s, –CH ), 4.31 (2H, s, –CH OH), 5.68 (1H, bs, OH), 6.28
6
3
2
(
Ar–H), 7.26–7.42 (7H, m, Ar–H, –NH), 9.29 (1H, bs, OH) ppm; C NMR
1H, s, –NCH), 6.40 (1H, d, J = 6.9 Hz, Ar–H), 6.50 (1H, m, Ar–H), 6.65 (1H, m,
1
3
(
100 MHz, DMSO-d ): d 24.2, 50.2, 59.6, 105.7, 109.0, 111.1, 111.8, 126.9, 127.4,
6
128.6, 137.5, 140.3, 140.9, 155.7, 156.9, 167.4, 173.9 ppm; Anal. Calcd. For
C H N O : C, 67.44; H, 5.36; N, 8.28; Found: C, 67.21; H, 5.39; N, 8.19 %.
1
9 18 2 4
123

R. Teimuri-Mofrad et al.
2
-[(2-Bromophenyl)(6-methylpyridin-2-ylamino)methyl]-3-hydroxy-6-(hydrox-
ymethyl)-4H-pyran-4-one (4b) White solid; Yield 89 %; mp: 160–162 °C; FT-IR
-
1 1
(
KBr) m 3443, 3342, 3083, 2918, 1646, 1612, 1579, 1471, 1224 cm ; H NMR
400 MHz, DMSO-d ): d 2.19 (3H, s, –CH ), 4.21 (2H, d, J = 13.2 Hz, –CH OH),
(
6
3
2
5
.67 (1H, bs, OH), 6.29–6.40 (3H, m, Ar–H, –NCH), 6.73 (1H, bs, –NH), 7.22–7.59
3
1
(
6H, m, Ar–H), 9.21 (1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 24.4,
6
5
1.4, 59.6, 105.6, 109.1, 111.1, 112.0, 123.4, 127.9, 129.6, 132.8, 137.6, 139.1,
42.1, 155.9, 156.8, 167.7, 174.1 ppm; Anal. Calcd. For C H BrN O : C, 54.69;
1
H, 4.11; N, 6.71; Found: C, 54.52; H, 4.14; N, 6.68 %.
1
9
17
2 4
2
4
3
-[(3-Bromophenyl)(6-methylpyridin-2-ylamino)methyl]-3-hydroxy-6-(hydroxymethyl)-
H-pyran-4-one (4c) White solid; Yield 91 %; mp: 183–185 °C; FT-IR (KBr) m
438, 3286, 3082, 2926, 2846, 1640, 1601, 1569, 1472, 1228 cm ; H NMR
-
1
1
(
J = 25.9 Hz, –CH OH), 5.67 (1H, bs, OH), 6.31 (1H, s, –NCH), 6.42 (1H, d,
400 MHz, DMSO-d ): d 2.22 (3H, s, –CH ), 4.30 (2H, dd, J = 14.2 Hz,
6
3
2
J = 6.6 Hz, Ar–H), 6.52 (1H, d, J = 7.0 Hz, Ar–H), 6.68 (1H, s, Ar–H), 7.31–7.61
1
3
(
6H, m, Ar–H, –NH), 9.38 (1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d
6
2
4.2, 49.8, 59.5, 105.8, 109.1, 110.3, 112.0, 121.8, 126.0, 129.4, 130.3, 130.8,
37.5, 141.2, 143.1, 155.6, 156.6, 167.5, 173.9 ppm; Anal. Calcd. For C H
9 17-
1
1
BrN O : C, 54.69; H, 4.11; N, 6.71; Found: C, 54.46; H, 4.15; N, 6.67 %.
2
4
2
4
3
-[(4-Chlorophenyl)(6-methylpyridin-2-ylamino)methyl]-3-hydroxy-6-(hydroxymethyl)-
H-pyran-4-one (4d) White solid; Yield 87 %; mp: 174–176 °C; FT-IR (KBr) m
442, 3343, 3072, 2971, 2852, 1652, 1578, 1475, 1216 cm ; H NMR (400 MHz,
-
1 1
DMSO-d ): d 2.22 (3H, s, –CH ), 4.29 (2H, dd, J = 15.5 Hz, J = 26.7 Hz,
6
3
–
CH OH), 5.66 (1H, bs, OH), 6.31 (1H, s, –NCH), 6.41 (1H, d, J = 7.1 Hz, Ar–H),
2
6.49 (1H, d, J = 8.2 Hz, Ar–H), 6.63–6.65 (1H, m, Ar–H), 7.28–7.33 (2H, m, Ar–
1
H, –NH), 7.38–7.44 (4H, 2d, J = 8.5 Hz, Ar–H), 9.34 (1H, bs, OH) ppm; H NMR
(
J = 26.7 Hz, –CH OH), 6.61 (1H, s, –NCH), 6.71 (1H, d, J = 7.1 Hz, Ar–H), 6.49
400 MHz, DMSO-d ? D O): d 2.80 (3H, s, –CH ), 4.58 (2H, dd, J = 15.5 Hz,
6
2
3
2
(
1H, d, J = 8.2 Hz, Ar–H), 6.91 (1H, s, Ar–H), 7.57–7.62 (1H, m, Ar–H),
1
3
7
.66–7.73 (4H, 2d, J = 8.5 Hz, Ar–H) ppm; C NMR (100 MHz, DMSO-d ): d
6
2
4.1, 49.7, 59.5, 105.8, 109.0, 111.9, 128.5, 128.7, 131.9, 137.5, 139.3, 141.0,
48.9, 155.6, 156.7, 167.5, 173.9 ppm; Anal. Calcd. For C H ClN O : C, 61.21;
1
H, 4.60; N, 7.51; Found: C, 61.03; H, 4.62; N, 7.48 %.
1
9
17
2 4
3
-Hydroxy-6-(hydroxymethyl)-2-[(4-methoxyphenyl)(6-methylpyridin-2-ylamino)-
methyl]-4H-pyran-4-one (4e) White solid; Yield 83 %; mp: 160–162 °C; FT-IR
-
1
(
1
KBr) m 3443, 3358, 3065, 2962, 2836, 1650, 1611, 1576, 1511, 1468, 1220 cm ;
H NMR (400 MHz, DMSO-d ): d 2.23 (3H, s, –CH ), 3.71 (3H, s, –OCH ), 4.28
6
3
3
(
2H, d, J = 8.8 Hz, –CH OH), 5.67 (1H, bs, OH), 6.31 (1H, s, –NCH), 6.40 (1H, d,
2
J = 7.1 Hz, Ar–H), 6.47 (1H, d, J = 7.9 Hz, Ar–H), 6.53 (1H, bs, –NH), 6.89 (2H,
d, J = 8.2 Hz, Ar–H), 7.18 (1H, d, J = 8.1 Hz, Ar–H), 7.28–7.35 (3H, m, Ar–H),
1
3
9
.24 (1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 24.2, 49.7, 55.1, 59.5,
6
1
05.6, 108.9, 110.7, 111.7, 113.9, 128.1, 137.4, 140.7, 149.9, 155.6, 156.9, 158.5,
67.3, 173.8 ppm; Anal. Calcd. For C H N O : C, 65.21; H, 5.47; N, 7.60; Found:
1
C, 64.97; H, 5.49; N, 7.56 %.
2
0 20 2 5
1
23

Eco-friendly one-pot, three component synthesis of novel…
3-Hydroxy-6-(hydroxymethyl)-2-[(6-methylpyridin-2-ylamino) (4-nitrophenyl)methyl]-
4
H-pyran-4-one (4f) Light brown solid; Yield 86 %; mp: 173–175 °C; FT-IR
-
1 1
(
KBr) m 3440, 3363, 3075, 2912, 2862, 1649, 1612, 1579, 1519, 1350 cm ; H
NMR (400 MHz, DMSO-d ): d 2.21 (3H, s, –CH ), 4.28 (2H, dd, J = 15.5 Hz,
6
3
J = 30.6 Hz, –CH OH), 5.66 (1H, bs, OH), 6.31 (1H, s, –NCH), 6.41 (1H, d,
2
J = 7.1 Hz, Ar–H), 6.52 (1H, d, J = 7.4 Hz, Ar–H), 6.77 (1H, bs, –NH), 7.34 (1H,
t, J = 7.6 Hz, Ar–H), 7.46 (1H, d, J = 6.8 Hz, Ar–H), 7.66 (2H, d, J = 7.8 Hz,
1
Ar–H), 8.21 (2H, d, J = 7.8 Hz, Ar–H), 9.48 (1H, bs, OH) ppm; C NMR
3
(
100 MHz, DMSO-d ): d 23.5, 49.3, 58.7, 105.3, 108.4, 111.5, 123.1, 127.4, 136.2,
6
136.9, 146.1, 147.4, 147.5, 155.0, 155.9, 167.1, 173.8 ppm; Anal. Calcd. For
C H N O : C, 59.53; H, 4.47; N, 10.96; Found: C, 59.35; H, 4.48; N, 10.91 %.
1
9 17 3 6
3-Hydroxy-6-(hydroxymethyl)-2-[(6-methylpyridin-2-ylamino) (3-nitrophenyl)methyl]-
4
H-pyran-4-one (4g) Light brown solid; Yield 90 %; mp: 164–166 °C; FT-IR
-
1 1
(
KBr) m 3440, 3285, 3064, 2929, 1639, 1604, 1567, 1471, 1348, 1236 cm ; H
NMR (400 MHz, DMSO-d ): d 2.22 (3H, s, –CH ), 4.31 (2H, dd, J = 15.2 Hz,
6
3
J = 31.4 Hz, –CH OH), 5.68 (1H, bs, OH), 6.31 (1H, s, –NCH), 6.44 (1H, d,
2
J = 7.1 Hz, Ar–H), 6.56 (1H, d, J = 5.5 Hz, Ar–H), 6.82 (1H, bs, –NH), 7.31–7.89
(
(
4H, m, Ar–H), 8.14 (1H, d, J = 6.8 Hz, Ar–H), 8.29–8.31 (1H, m, Ar–H), 9.49
1
3
1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 24.1, 49.9, 59.5, 105.9,
6
1
1
1
09.2, 109.9, 110.9, 112.2, 121.4, 122.5, 130.0, 130.2, 133.7, 137.6, 147.9, 155.7,
56.6, 167.7, 174.0 ppm; Anal. Calcd. For C H N O : C, 59.53; H, 4.47; N,
0.96; Found: C, 59.30; H, 4.49; N, 10.90 %.
1
9 17 3 6
3
-Hydroxy-6-(hydroxymethyl)-2-[(6-methylpyridin-2-ylamino)
(naphthalen-1-
yl)methyl]-4H-pyran-4-one (4h) White solid; Yield 88 %; mp: 182–184 °C;
-
1 1
FT-IR (KBr) m 3439, 3271, 3058, 2844, 1647, 1576, 1471, 1208 cm ; H NMR
400 MHz, DMSO-d ): d 2.23 (3H, s, –CH ), 4.29 (2H, m, –CH OH), 5.68 (1H, bs,
OH), 6.31 (1H, s, –NCH), 6.41 (1H, d, J = 7.0 Hz, Ar–H), 6.54 (1H, d, J = 6.9 Hz,
(
6
3
2
Ar–H), 6.82 (1H, bs, –NH), 7.31–7.59 (5H, m, Ar–H), 7.89 (4H, m, Ar–H), 9.35
3
1
(
1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 24.2, 50.5, 59.6, 105.8,
6
1
1
5
09.1, 111.9, 125.2, 125.3, 126.1, 126.4, 127.6, 127.9, 128.3, 132.4, 132.9, 137.5,
37.8, 155.7, 156.9, 167.5, 174.1 ppm; Anal. Calcd. For C H N O : C, 71.12; H,
2
3 20 2 4
.19; N, 7.21; Found: C, 70.88; H, 5.21; N, 7.18 %.
3
-Hydroxy-6-(hydroxymethyl)-2-[phenyl(pyridin-2-ylamino) methyl]-4H-pyran-4-
one (4i) White solid; Yield 85 %; mp: 168–170 °C; FT-IR (KBr) m 3425, 3354,
-
1 1
3
031, 2914, 1648, 1615, 1538, 1419 cm ; H NMR (400 MHz, DMSO-d ): d 4.29
6
(
H, –NH), 7.26–7.62 (7H, m, Ar–H), 7.96 (1H, s, Ar–H), 9.23 (1H, bs, OH) ppm;
2H, m, –CH OH), 5.67 (1H, bs, OH), 6.29 (1H, s, –NCH), 6.54–6.74 (3H, m, Ar–
2
1
3
C
NMR (100 MHz, DMSO-d ): d 49.8, 59.5, 109.0, 110.4, 112.3, 126.6, 127.0, 128.3,
6
1
32.3, 137.0, 140.8, 142.3, 147.4, 157.3, 167.6, 173.7 ppm; Anal. Calcd. For
C H N O : C, 66.66; H, 4.97; N, 8.64; Found: C, 66.41; H, 4.99; N, 8.60 %.
1
8 16 2 4
2
-[(3-Bromophenyl)(pyridin-2-ylamino)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-
pyran-4-one (4j) White solid; Yield 91 %; mp: 172–174 °C; FT-IR (KBr) m 3405,
-
304, 3023, 2925, 1641, 1607, 1522, 1443, 1203 cm ; H NMR (400 MHz,
1
1
3
123

R. Teimuri-Mofrad et al.
DMSO-d ): d 4.29 (2H, s, –CH OH), 5.66 (1H, bs, OH), 6.30 (1H, s, –NCH),
6
2
6
.56–6.74 (3H, m, Ar–H, –NH), 7.31–7.57 (6H, m, Ar–H), 7.96 (1H, s, Ar–H), 9.35
1
3
(
1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 49.7, 59.5, 109.0, 109.3,
6
1
13.0, 121.8, 125.9, 129.2, 130.3, 130.8, 137.1, 141.0, 143.0, 147.4, 148.8, 157.2,
67.5, 173.8 ppm; Anal. Calcd. For C H BrN O : C, 53.62; H, 3.75; N, 6.95;
1
Found: C, 53.38; H, 3.78; N, 6.91 %.
1
8
15
2 4
2
-[(4-Chlorophenyl)(pyridin-2-ylamino)methyl]-3-hydroxy-6-(hydroxymethyl)-4H-
pyran-4-one (4k) White solid; Yield 85 %; mp: 182–184 °C; FT-IR (KBr) m 3330,
-
174, 3063, 2935, 1663, 1618, 1568, 1453, 1098 cm ; H NMR (400 MHz,
1
1
3
DMSO-d ): d 4.27 (2H, s, –CH OH), 5.66 (1H, bs, OH), 6.14 (1H, s, –NCH), 6.34
6
2
(
1H, s, Ar–H), 6.62–6.82 (3H, m, Ar–H, –NH), 7.38–7.61 (5H, m, Ar–H), 7.89 (1H,
1
3
s, Ar–H), 9.39 (1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 40.4, 59.5,
6
1
09.2, 110.5, 111.9, 128.5, 128.8, 130.2, 132.3, 135.4, 140.2, 142.4, 146.4, 157.1,
67.8, 173.6 ppm; Anal. Calcd. For C H ClN O : C, 60.26; H, 4.21; N, 7.81;
1
Found: C, 60.02; H, 4.22; N, 7.78 %.
1
8
15
2 4
2
4
3
-[(4-Methylphenyl)(pyrimidin-2-ylamino)methyl]-3-hydroxy-6-(hydroxymethyl)-
H-pyran-4-one (4l) White solid; Yield 85 %; mp: 151–153 °C; FT-IR (KBr) m
418, 3321, 3051, 2935, 2876, 1638, 1583, 1217 cm ; H NMR (400 MHz,
-
1
1
DMSO-d ): d 2.25 (3H, s, –CH ), 4.25–4.31 (2H, m, –CH OH), 5.68 (1H, bs, OH),
6
3
2
6
H), 7.28 (2H, d, J = 7.4 Hz, Ar–H), 8.04 (1H, d, J = 8.3 Hz, Ar–H), 8.31 (2H, d,
.28 (1H, s, –NCH), 6.65 (2H, d, J = 4.4 Hz, Ar–H), 7.13 (2H, d, J = 7.4 Hz, Ar–
1
3
J = 4.1 Hz, Ar–H), 9.31 (1H, bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d
6
2
0.7, 50.1, 59.5, 108.9, 110.1, 111.2, 126.6, 129.1, 136.6, 136.8, 142.7, 148.5,
58.2, 161.3, 167.3, 173.9 ppm; Anal. Calcd. For C H N O : C, 63.71; H, 5.05;
1
N, 12.38; Found: C, 63.45; H, 5.06; N, 12.31 %.
1
8 17 3 4
Procedure for synthesis of compound 4a (Multigram scale)
A mixture of aldehyde (2.12 g, 20 mmol), kojic acid (2.82 g, 20 mmol), and amine
(
2.26 g, 21 mmol) and Ce (SO ) (10 mol%) was poured into a stainless steel
2 4 3
double-walled ball-mill beaker at room temperature. After 25 min, TLC indicated
that the reaction was completed. The reaction mixture was washed with acetone
(
2 9 25 mL) to remove unreacted materials and with cold water (2 9 50 mL) to
remove the catalyst. Finally, the solid product was dried to obtain the pure product.
The catalyst-containing water was dried under reduced pressure, and the resulting
solid was reused for additional synthetic cycles, with the amounts of the reactants
adjusted each time to the recovered amount of Ce (SO ) . The successive yields of
2
4 3
1
aminokojic acid (4a) for each cycle were 90, 87, 88, and 86 %. The H NMR
spectroscopic data were the same for each sample.
General procedure for the synthesis of aminokojic acid derivatives (5a–d)
A mixture of terephthaldehyde (1 mmol), kojic acid (2 mmol), and amine
(
2.2 mmol) and Ce (SO ) .5H O (20 mol%) was poured into a stainless steel
2 4 3 2
1
23

Eco-friendly one-pot, three component synthesis of novel…
double-walled ball-mill beaker at ambient temperatures at a speed of 25 Hz for the
appropriate time according to Scheme 2. After completion of the reaction, as
indicated by TLC (acetone–n-hexane, 3:1), the reaction mixture was washed with
acetone (2 9 7 mL) to remove unreacted materials and with cold water
(
2 9 14 mL) to remove the catalyst. Finally, the solid was dried to obtain the
1
13
pure product. The isolated compounds were characterized by mp, IR, H NMR,
NMR and elemental analysis (C, H, and N).
C
1
,4-Bis-[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl-(6-methylpyridin-2-
ylamino)methyl]benzene (5a) White solid; Yield 87 %; mp: 188–190 °C; FT-IR
-
1
1
(
KBr) m 3448, 3289, 3053, 2967, 1644, 1607, 1473, 1212 cm
;
H NMR
(
400 MHz, DMSO-d ): d 2.21 (6H, s, –CH ), 4.28 (4H, s, –CH OH), 5.63 (2H, bs,
6
3
2
OH), 6.27 (2H, s, –NCH), 6.39 (2H, d, J = 7.0 Hz, Ar–H), 6.46 (2H, d, J = 7.8 Hz,
Ar–H), 6.60 (2H, d, J = 7.0 Hz, Ar–H), 7.19 (2H, bs, –NH), 7.29 (2H, t,
1
3
J = 7.7 Hz, Ar–H), 7.39 (4H, s, Phenyl-H), 9.22 (2H, bs, OH) ppm; C NMR
(
100 MHz, DMSO-d ): d 24.2, 50.0, 59.5, 105.6, 108.9, 110.8, 111.7, 127.1, 137.4,
6
139.3, 140.9, 149.4, 155.6, 156.8, 167.4, 173.8 ppm; Anal. Calcd. For C H N O :
32 30 4 8
C, 64.21; H, 5.05; N, 9.36; Found: C, 63.97; H, 5.08; N, 9.32 %.
1
,4-Bis-[3-hydroxy-6-(chloromethyl)-4-oxo-4H-pyran-2-yl-(6-methylpyridin-2-
ylamino)methyl]benzene (5b) White solid; Yield 84 %; dec: 217–219 °C; FT-IR
-
1
1
(
KBr) m 3382, 3284, 3029, 2957, 1641, 1591, 1469, 1208 cm
;
H NMR
(
J = 6.9 Hz, Ar–H), 6.51–6.61 (8H, m, –NCH, Ar–H), 7.27–7.47 (6H, m, –NH, Ar–
400 MHz, DMSO-d ): d 2.21 (6H, s, –CH ), 4.62 (4H, s, –CH Cl), 6.39 (2H, d,
6
3
2
1
H), 7.68 (2H, d, J = 7.9 Hz, Ar–H), 9.52 (2H, bs, OH) ppm; C NMR (100 MHz,
3
DMSO-d ): d 23.9, 50.6, 62.6, 105.9, 109.6, 111.5, 112.6, 127.4, 128.9, 129.8,
6
1
37.6, 143.5, 146.2, 156.6, 160.9, 173.7 ppm; Anal. Calcd. For C H Cl N O : C,
32 28 2 4 6
6
0.48; H, 4.44; N, 8.82; Found: C, 60.21; H, 4.45; N, 8.79 %.
1
,4-Bis-[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl-(pyridin-2-ylamino)
methyl]benzene (5c) White solid; Yield 82 %; mp: 186–188 °C; FT-IR (KBr) m
-
414, 3335, 3022, 2968, 1641, 1614, 1516, 1438 cm ; H NMR (400 MHz,
1
1
3
DMSO-d ): d 4.27 (4H, s, –CH OH), 5.63 (2H, bs, OH), 6.28 (2H, s, –NCH), 6.52
6
2
(
2H, t, J = 6.0 Hz, Ar–H), 6.62 (2H, m, Ar–H), 6.68 (2H, d, J = 8.4 Hz, Ar–H),
.32–7.42 (8H, m, Ar–H, –NH), 7.94 (2H, d, J = 4.0 Hz, Ar–H), 9.23 (2H, bs, OH)
7
1
ppm; H NMR (400 MHz, DMSO-d ? D O): d 4.27 (4H, s, –CH OH), 6.28 (2H, s,
6
2
2
–
NCH), 6.52 (2H, t, J = 6.0 Hz, Ar–H), 6.65–6.67 (4H, m, Ar–H), 7.37 (6H, m,
1
3
Ar–H), 7.91 (2H, d, J = 4.0 Hz, Ar–H) ppm; C NMR (100 MHz, DMSO-d ): d
6
4
9.9, 59.5, 108.9, 109.1, 112.7, 127.0, 127.1, 136.9, 139.3, 140.9, 147.4, 149.4,
57.3, 167.4, 173.8 ppm; Anal. Calcd. For C H N O : C, 63.15; H, 4.59; N, 9.82;
1
Found: C, 62.91; H, 4.61; N, 9.78 %.
3
0 26 4 8
1
,4-Bis-[3-hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl-(pyrimidin-2-ylamino)
methyl]benzene (5d) White solid; Yield 83 %; dec: 221–223 °C; FT-IR (KBr) m
-
412, 3303, 3027, 2922, 1627, 1583, 1452, 1217 cm ; H NMR (400 MHz,
1
1
3
DMSO-d ): d 4.30 (4H, dd, J = 15.5 Hz, J = 27.5 Hz, –CH OH), 5.68 (2H, bs,
6
2
OH), 6.31 (2H, s, –NCH), 6.62–6.69 (4H, m, Ar–H), 7.41–7.42 (4H, m, Ar–H,
123

R. Teimuri-Mofrad et al.
–
NH), 8.10 (2H, d, J = 6.5 Hz, Ar–H), 8.29 (4H, d, J = 4.5 Hz, Ar–H), 9.37 (2H,
1
3
bs, OH) ppm; C NMR (100 MHz, DMSO-d ): d 50.2, 59.6, 109.1, 110.2, 111.3,
6
127.1, 139.1, 140.9, 148.6, 158.1, 158.3, 161.3, 167.5, 173.9 ppm; Anal. Calcd. For
C H N O : C, 58.74; H, 4.23; N, 14.68; Found: C, 58.53; H, 4.24; N, 14.63 %.
2
8 24 6 8
4
-[(3-Hydroxy-6-(hydroxymethyl)-4-oxo-4H-pyran-2-yl)(6-methylpyridin-2-ylamino)
methyl]benzaldehyde (6) White solid; dec: 187–189 °C; FT-IR (KBr) m 3450,
-
257, 3067, 2976, 2832, 2744, 1703, 1643, 1579, 1472, 1213 cm ; H NMR
1
1
3
(
J = 14.1 Hz, –CH OH), 5.65 (1H, t, J = 5.8 Hz, OH), 6.31 (1H, s, –NCH), 6.41
400 MHz, DMSO-d ): d 2.21 (3H, s, –CH ), 4.28 (2H, dd, J = 5.6 Hz,
6
3
2
(
1H, d, J = 7.1 Hz, Ar–H), 6.52 (1H, d, J = 7.6 Hz, Ar–H), 6.75 (1H, bs, –NH),
.32 (1H, t, J = 7.7 Hz, Ar–H), 7.39 (1H, s, Ar–H), 7.64 (2H, d, J = 7.5 Hz, Ar–
H), 7.89 (2H, d, J = 7.5 Hz, Ar–H), 9.40 (1H, bs, OH), 9.97 (1H, s, aldehyde-H)
7
1
3
ppm; C NMR (100 MHz, DMSO-d ): d 24.1, 50.2, 59.4, 105.8, 108.9, 111.9,
6
1
1
6
27.5, 129.8, 130.0, 135.4, 137.3, 141.2, 147.1, 155.6, 156.7, 167.6, 173.8,
92.6 ppm; Anal. Calcd. For C H N O : C, 65.57; H, 4.95; N, 7.65; Found: C,
2
0 18 2 5
5.32; H, 4.97; N, 7.61 %.
Acknowledgments The authors gratefully acknowledge the Iran National Science Foundation (INSF)
for financial support. The research work of the University of Tabriz is also gratefully appreciated.
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