Synthesis and catalytic application of D-glucose derived ytterbium(III) complex in Biginelli reaction

Article abstract of DOI:10.1016/j.inoche.2020.108165

4,6-O-Ethylidene-N-(2-hydroxybenzylidene)-β-D-glucopyranosylamine has been reacted with ytterbium(III) acetate and the resultant complex has been used as catalyst in the synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones (DHPMs). Twenty-one DHPMs have been synthesised under neat reaction condition in appreciable yields (73–96percent) and reusability of the catalyst has been established.

Full text of DOI:10.1016/j.inoche.2020.108165

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Short communication
Synthesis and Catalytic Application of D-Glucose Derived Ytterbium(III)
Complex in Biginelli Reaction
Vimal Kumar Madduluri, Santosh Kumar Mishra, Ajay K. Sah
PII:
S1387-7003(20)30755-3
DOI:
https://doi.org/10.1016/j.inoche.2020.108165
INOCHE 108165
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Inorganic Chemistry Communications
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5 August 2020
Please cite this article as: V. Kumar Madduluri, S. Kumar Mishra, A.K. Sah, Synthesis and Catalytic Application
of D-Glucose Derived Ytterbium(III) Complex in Biginelli Reaction, Inorganic Chemistry Communications
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2020), doi: https://doi.org/10.1016/j.inoche.2020.108165
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Synthesis and Catalytic Application of D-Glucose Derived Ytterbium(III)
Complex in Biginelli Reaction
Vimal Kumar Madduluri, Santosh Kumar Mishra, Ajay K. Sah*
Department of Chemistry, Birla Institute of Technology and Science, Pilani; Pilani Campus,
Rajasthan 333031, India.
*Corresponding author. Email: asah@pilani.bits-pilani.ac.in (A. K. Sah)
Abstract
4,6-O-Ethylidene-N-(2-hydroxybenzylidene)--D-glucopyranosylamine
has
been
reacted with ytterbium(III) acetate and the resultant complex has been used as catalyst in the
synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones (DHPMs). Twenty-one DHPMs have
been synthesised under neat reaction condition in appreciable yields (73–96%) and reusability
of the catalyst has been established.
Key words : D-Glucose  Lanthanides  Ytterbium  Homogenous catalysis  Biginelli reaction.

1.
Introduction
Lanthanide complexes are widely used in the fields of bioimaging [1], molecular
sensing [2], magnetic resonance imaging [3], clinical diagnosis [4] and polymer synthesis [5]
owing to their unique properties like long-lived luminescence [6], single-molecule magnetism
[
7], flexible coordination capability [8], Lewis acidity [9] and photosensitivity [10]. Such
complexes have also been used as catalysts in several organic reactions like hydrogenation
11], photo induced oxidation reduction [12], polymerization [13] and Diels-Alder reactions [14].
[
Researchers have established the ligand (monodentate halide ions, bidentate acetate anions,
polydentate crown ethers and porphyrins) induced perturbation in the physical and chemical
properties of lanthanide complexes [15, 16]. In most of the complexes, lanthanides are
coordinated to oxygen atoms of the ligand [17], however, utilization of carbohydrate based
ligands are scarce. Rao’s group has explored the interaction of mono- and di- saccharides
with La(III), Ce(III), Pr(III), Nd(III), Sm(III), Eu(III) and Dy(III) ions [18] while Zhao group
reported the crystal structure of Pr(III)(D-rib.5H O) [19]. Since, binding abilities of 4,6-O-
2
ethylidene-N-(2-hydroxybenzylidene)--D-glucopyranosylamine (H L1) with transition metal
3
ions (Cu(II), Ni(II), Zn(II), V(V), Mo(VI)) alongside U(VI) are known [20], we are interested in
exploring the interaction of this ligand with lanthanides and application of the resultant complex
in catalysis.
The interaction studies of H L1 with trivalent lanthanides in methanol using UV-visible
3
spectroscopy afforded best result for ytterbium(III), which finds various applications in organic
syntheses as Lewis acid catalyst [21, 22]. The catalysed reactions include the synthesis of
several heterocycles as well as 3,4-dihydropyrimidin-2(1H)-ones/thiones (DHPMs) via Biginelli
reaction [23]. DHPMs are extensively used in medicinal field as calcium channel modulators,
anti-cancer, anti-inflammatory, anti-microbial and anti-viral agents [24-26]. Inspired from these
facts, we reacted the ytterbium(III) acetate with H L1 in methanol and isolated the
3
corresponding product. The isolated complex was used as catalyst in Biginelli reaction and

twenty-one heterocycles have been isolated. Hence, this paper deals with the synthesis of
glucose derived ytterbium complex and its application as catalyst in the synthesis of DHPMs.
2.
Experimental
2.1
Materials and methods
Entire synthetic experiments were performed under normal atmospheric conditions.
Ytterbium(III) acetate was purchased from Alfa Aesar, D-Glucose, Acetonitrile and methanol
HPLC grade) from Merck India and all other chemicals along with solvents were procured
(
from local supplier. Solvents were distilled following the standard methods before use. UV-
visible spectra were recorded on Jasco V-650 spectrophotometer and data was processed
1
13
using OriginLab software. H and C NMR were recorded on a Bruker Avance spectrometer
and data was processed using MestReNova 10 software. The IR spectra were recorded on
Shimadzu infinity FTIR machine using KBr Matrix and HRMS data on an Agilent 6545 LC-
QTOF system. Melting point was recorded in open capillary tubes on EZ-Melt automated
melting point apparatus and are uncorrected. HPLC data was collected on Waters binary
pump LC system equipped with PDA detector and processed using Empower 2 software at
280 nm. Chromatographic conditions for reverse phase separation are as follows-: Column,
Waters Sunfire C18 5m 4.6250 mm; Elution method, gradient; Mobile phase, acetonitrile
and water; Flow rate, 0.4 mL/min and for chiral separation: Column, Kromasil 5-Amycoat RP
5m 4.6250 mm; Elution method, isocratic; Mobile phase, water and acetonitrile (v/v) in the
ratio 1 : 11; Flow rate, 0.6 mL/min. Elemental composition was obtained from Thermo finnigan
FLASH EA 1112 series CHNS(O) analyzer and thermal analysis was performed on Shimadzu
TGA-50 in the temperature range of 40-800 °C under N atmosphere at heating rate 10 °C/min.
2
Powder X-ray diffraction data was aquired using Rigaku Miniflex II with copper anode (Cu-K,

= 1.54 Å) as X-ray source. SEM images and EDX analysis were obtained from Leica ultra

microtome EM UC7, FEI Apreo LoVac with Aztec standard EDS system (resolution 127 eV on
Mn-K.
2.2
Synthesis of 4,6-O-ethylidene-N-(2-hydroxybenzylidene)-D-glucopyranosylamine
(
H L1).
3
D-Glucose was converted to 4,6-O-ethylidene--D-glucopyranosylamine, which was
further condensed with salicyaldehyde following the literature procedure to obtain the ligand
H L1 [27, 28]. The purity of the ligand was established by NMR analysis and HRMS (m/z calcd
3
+
for C H NO (M+H) = 310.1285; found 310.1285) data.
15
19
6
2.3
Synthesis of ytterbium(III) complex (YbH L1)
3
Methanolic solution of ytterbium(III) acetate (1.1 mmol) was added to a stirring solution
of H L1 (1 mmol) in methanol at room temperature. The reaction mixture was stirred over night
3
and pale yellow precipitate formed was filtered. The residue (product) was washed with
methanol and dried. Yield, 78%; Pale yellow solid; mp, charred above 210 °C; IR (KBr matrix,

1
-
-
cm ): 1631 (C=N), 1546 (C=O(asym) of COO ), 1454 (
of COO ), 1072 (C-O); Elemental
C=O(sym)
analysis (weight %): CHNO calculated for Yb(C H NO )(C H O ) (CH OH) , C(37.522),
15
18
6
2
3
2 0.25
3
0.5
H(4.084), N(2.735), O(21.868) found C(38.099), H(4.553), N(2.368), O(21.405); UV-visible
peaks: 269 (  *), 357 (  *) nm [29]; HRMS: m/z calcd for C H N O Yb
45
54
3
18
+
+
(
[Yb(H L1) +H] ) and C H N O Yb ([Yb(H L1) ] ), 1099.2869 and 790.1657; found
3 3 30 36 2 12 3 2
1099.2867 and 790.1659 respectively.
2.4
General procedure for synthesis of 3,4-dihydropyrimidin-2-(1H)-ones/thiones

Ethyl/benzyl acetoacetate (1.0 mmol), aldehyde derivative (1.0 mmol) and
urea/thiourea (1.0 mmol) were stirred at 90 °C in presence of YbH L1 (1 mol% as per empirical
3
formula) under neat condition. The product solidified within an hour, which was cooled to room
temperature and ethanol (3–5 mL) was added to that. The suspension was filtered to isolate
the solid product, which was further recrystallised from ethanol.
3.
Results and discussion
3.1
Synthesis and characterization of ytterbium complex (YbH L1)
3
4
,6-O-Ethylidene-N-(2-hydroxybenzylidene)--D-glucopyranosylamine (H L1) was
3
screened for interaction with trivalent lanthanides using UV-visible spectroscopy. Methanolic

4
4
solution of H L1 (10 M) and lanthanide(III) acetates (10 M) were mixed in 1:1 ratio and UV-
3
visible spectra were recorded for the resultant mixtures. Hypochromic shift in the ligand’s band
at 319 nm and appearance of a new band at 357 nm indicated the ligand interaction with
metal. The stacked spectra of mixtures along with ligand are shown in Fig. 1a, which clearly
indicates the major change in case of ytterbium(III) acetate. Inspired from these results, data
for Job’s plot [30] (Fig. 1b) was generated using the absorbance value of mixtures at 357 nm.
Fig. 1 (a) Absorbance spectra of methanolic solution containing lanthanide acetate and H L1
3
3+
in 1:1 ratio; (b) Job’s plot for interaction of Yb with H L1
3

3+
Fig. 2 (a) Absorbance spectra for titration of H L1 with Yb ; (b) Exponential fit titration curve
3
at 357 nm
This study supported the ligand interaction with ytterbium in 1:1 ratio and appearance of
isosbestic points during titration of H L1 with Yb(III) (Fig. 2a) supported the conservation of
3
stoichiometry in the course of complex formation.
Yoe-Jones method [31] has been used on absorbance values of mixture at 357 nm
6
1
(
Fig. 2b) to obtain the binding constant (K ) of the complex as 1.77  10 M . This result (log
est
Kest = 6.3) is comparable with that of Borisova et al., who have reported log Kest values in the
range 5.6–8.5 for ytterbium complexes with tetradentate N,N′,O,O′-dipyridyl-based ligands
[
32]. Literature reports on metal ion binding mode of H L1 suggests that it can exhibit
3
maximum tetradenticity [33, 34] while ytterbium ought to have more than six coordination
number, which indicates the possibility of multinuclear complex formation. In order to further
learn about the entity of complex, we isolated the solid product after reacting the ligand and
metal salt in 1:1 ratio (details are provided in section 2.3) and explored its composition. FTIR

1
spectrum of the complex exhibited peaks at 1631 and 1072 cm corresponding to 
and
C=N

1
C-O stretches of the metal bound ligand. Few peaks also appeared at 1546 and 1454 cm ,
agreeing to C=O (asym) and C=O (sym) stretches of metal bound acetate moiety [35] (Fig. S1).
This study supported the involvement of both H L1 and acetate ion in complexing the
3
ytterbium. Weight percentage of C, H, N, O determined by elemental analysis (mentioned in

section 2.3) tallies with Yb(C H NO )(C H O ) (CH OH) , which also supports the
15
18
6
2
3
2 0.25
3
0.5
interaction of metal and ligand in 1:1 ratio. HRMS study of the isolated complex provided peaks
+
+
at m/z 1099.2867 ([Yb(H L1) +H] ) and 790.1694 ([Yb(H L1) ] ) supporting the association of
3
3
3
2
ytterbium with two to three ligands which may be possible in multinuclear complex.
Fragmentation analysis using collison chamber voltage 20V resulted in daughter ion peaks at
790.1679 (C H N O Yb) and 498.0517 (C H NO Yb) for parent m/z 1099.2867, and at
30 36 2 12 15 18 7
4
98.0468 (C H NO Yb) for parent m/z 790.1694, which supported the above prediction.
15
18
7
Differential thermal analysis curve of the complex exhibited five stages of decomposition (Fig.
S2), where initial weight loss (2.8%; 40-150 °C) may be due to the elimination of methanol,
which is in well agreement with the therotical value (3.1 w%). Combined weight loss for the
remaining four steps (62.9%; 150-800 °C) may be attributed to the removal of ligand and
acetate ions (calculated 63.1%) leaving Yb O as white powder [36]. Crystallinity and particle
2
3
size distribution of the complex have been calculated as 60% and 345 nm (by Scherrer
Equation) [37] using Powder X-ray diffraction data (Fig.S3). SEM images revealed rod shaped
morphology of the complex with uniform distribution of ytterbium all over the surface (Fig. 3).
Several attempts to crystallize the complex failed and hence, actual coordination sphere of
the metal centre could not be established.
Fig. 3 SEM (left) and EDX (right) images showing the morphology and ytterbium distribution
in YbH L1
3

3.2
Catalytic synthesis of 3,4-dihydropyrimidin-2(1H)-ones/thiones
Metal complexes of H L1 have been used as catalyst in several organic reactions such
3
as Mo(VI) complex in selective oxidation of organic sulfides to sulfoxides, sulfones and
alkenes to epoxides while dinuclear Cu(II) complex has been used in selective oxidation of
catechol and benzylic alcohols to corresponding carbonyl derivatives [20]. Several reports on
ytterbium(III) catalysed reactions are also available, where it has been used in glycosylation
[
38], cycloadditions [39, 40], hydrophosphonylation [41, 42] along with typical Mannich,
Michael, Friedel-Crafts and Diels-Alder reactions [21]. Few reports are also available on
ytterbium complex catalysed Biginelli reaction [23] including a report on Schiff base derived
complex [43], which prompted us to explore the catalytic action of YbH L1 towards Biginelli
3
reaction. Firstly, optimisation of reaction was performed for best suited solvent, temperature,
reaction time and catalyst loading using ethyl acetoacetate, benzaldehyde and urea as typical
reactants. Progress of reaction was monitered using thin-layered chromatography and yields
were calculated by quantitative HPLC seperation. Standard/test solutions required for
calculation of yield were prepared by dissolving pure ethyl 6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (B1) or the reaction mixture in 1 mL dimethylsulfoxide,
which was further diluted with methanol and calibration curve was plotted using the standard
solutions with concentrations 10, 50, 100, 200, 300, 400 and 500 M. Blank reactions were
performed using ytterbium(III) acetate and ytterbium(III) triflate to find the effect of ligand on
product formation. Summary of optimisation reactions are presented in Table 1, which
validates the optimum conditions as 1 mol % catalyst loading with reaction time and
temperature as 90 C and one hour respectively under neat condition (Scheme 1).
O
R'
O
O
X
R
YbH L1
3
O
NH
R
R' CHO
O
H N
NH2
90C,
Neat
2
N
H
X
R = ethyl /
benzyl
R = aryl /
alkenyl
X = O or S
Scheme 1 Optimised protocol for YbH L1 catalysed synthesis of DHPMs
3

Table 1 Optimisation of conditions for ytterbium complex catalysed Biginelli reactiona
Catalyst (mol %)b
Solvent
Yield (%)
c
Time (h)
Temperature (C)
Entry
1
2
3
4
5
6
7
8
9
YbH L1 (1.0)
ACN
DCM
DMF
Ethanol
Water
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
Neat
16
53
1
1
reflux
reflux
reflux
reflux
reflux
90
3
YbH L1 (1.0)
3
YbH L1 (1.0)
83
1
3
YbH L1 (1.0)
65
1
3
YbH L1 (1.0)
55
1
3
YbH L1 (1.0)
98
1
3
YbH L1 (0.5)
64
1
90
3
YbH L1 (2.0)
96
1
90
3
YbH L1 (3.0)
93
1
90
3
10
11
12
13
14
15
16
17
18
19
20
21
22
23
YbH L1 (10.0)
67
1
90
3
YbH L1 (1.0)
39
0.25
0.5
0.75
1.5
1
90
3
YbH L1 (1.0)
64
90
3
YbH L1 (1.0)
85
90
3
YbH L1 (1.0)
97
90
3
Yb(OTf) (1.0)
62
90
3
Yb(CH COO) (5.0)
25d
37
1
90
3
3
Yb(CH COO) (5.0)
12
24
1
90
3
3
Yb(CH COO) (5.0)
39
90
3
3
YbH L1 (1.0)
traced
37
RT
RT
RT
50
3
YbH L1 (1.0)
4
3
YbH L1 (1.0)
42
24
1
3
YbH L1 (1.0)
traced
28d
3
YbH L1 (1.0)
1
70
3
a
b
c
d
ethyl acetoacetate (1 mmol), urea (1 mmol), benzaldehyde (1 mmol)
mole percentage with respect to benzaldehyde
yield by HPLC
isolated yields

Under optimum reaction conditions set by us, twenty-one different DHPMs were
synthesised in good to excellent yields (73–96%) and all the molecules were characterized
with the help of NMR and HRMS analysis (Table 2). Aldehydes bearing electron donating
groups (EDG) afforded lower yields while opposite drift was observed in case electron
withdrawing substituents and similar trend was reported by Zhang et al. [44]. Increase in the
number of EDGs on aldehyde (entry B7, B8), further decreased the yield as expected.
Replacement of urea with thiourea also resulted in the lowering of corresponding product
formation, which complies with the results reported by Wang & co-workers [45, 46]. While
working with ytterbium triflate, they reported the completion time for Biginelli reaction as 20
min in case of urea [45] and one hour for thiourea [46]. Reusability of the catalyst was tested
with ethyl acetoacetate, benzaldehyde and urea following the synthetic method mentioned in
section 2.4. After completion of first cycle, product was isolated from ethanol and the filtrate
was evaporated under reduced pressure to result in slurry of catalyst, which was charged with
fresh reactants to perform the second cycle of reaction. This procedure was repeated for five
times to ensure the recyclability of catalyst and result is shown in Fig. 4. During recycling
process, no appreciable loss in the catalytic activity was detected, contrary increase in
efficiency was noticed in the course of first few cycles, which may be due to the trapping of
reactants from previous cycle.
Fig. 4 Recyclability result of YbH L1 catalysed Biginelli reaction
3

Table 2 Synthesis of DHPMs using ytterbium complex under optimised reaction
conditionsa
Entry
R
R
X
Yield(%)b
B1
B2
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Ethyl
Benzyl
Benzyl
Ethyl
phenyl
O
O
O
O
O
O
O
O
O
O
O
O
O
O
O
S
92
95
94
95
96
96
87
82
94
80
90
89
91
90
82
78
85
83
90
73
92
2-chlorophenyl
3-chlorophenyl
4-chlorophenyl
3-chloro-2-fluorophenyl
4-bromo-2-fluorophenyl
3,4,5-tri-methoxyphenyl
2,4,6-tri-methoxyphenyl
4-methylphenyl
4-hydroxyphenyl
4-methoxyphenyl
4-bromophenyl
styryl
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
B13
B14
B15
B16
B17
B18
B19
B20
B21
1-naphthyl
thiophene-2-yl
phenyl
2-chlorophenyl
4-chlorophenyl
phenyl
S
S
O
S
phenyl
2-hydroxyphenyl
O
a
Aldehyde (1.0 mmol), urea/thiourea (1.0 mmol), acetoacetic ester (1.0) and ytterbium
complex (1 mol%) at 90 C, neat condition, 1 hour.
b
isolated yield

A comparison of our protocol with previous literature reports on ytterbium catalysed
Biginelli reaction has been summarized in Table 3. Current catalytic system has advantages
over other methodologies in terms of catalyst loading, reaction time as well as purification
process. The current catalyst has been reused for five times without appreciable loss in
activity. Ytterbium complex catalysed Biginelli reaction with 2-hydroxybenzaldehydes often
leads to the formation of oxygen-bridged tricyclic tetrahydro pyrimidines [43], but we have
noticed the formation of mainly Biginelli product. Since, H L1 is chiral in nature, we were
3
expecting the enantioselective product, but unfortunately, we noticed the formation of racemic
mixture, which was supported by chiral HPLC analysis (Fig. S5c).
Table 3 Comparison of Biginelli reactions catalysed by different ytterbium compounds
Entry
Catalyst (mol %)
Time
Solvent
Temperature Reference
1
2
3
4
5
6
7
8
9
Yb(OTf) (5 mol%)
1 h
48 h
12 h
-
Neat
Neat
100°C
120°C
Reflux
Reflux
RT
[45, 46]
[47]
3
Resin bound Yb3+
Yb(OTf) (20 mol%)
Toluene
Ethanol
THFb
[48]
3
Yb(CH SO ) (10 mol%)
[49]
3
3 3
a
Yb(OTf) +L (5 mol%)
20-30 h
2-6 h
3 h
[50]
3
Yb(NPf ) (1 mol%)
C F
10 18
90°C
90°C
RT
[51]
2
3
YbCl (3 mol%)
Neat
THFb
Neat
Neat
[44]
3
a
Yb(pic) .L (10 mol%)
60 h
4 h
[43]
3
Yb(PFO) (5 mol%)
120°C
90°C
[52]
3
10
Yb.H L1 (1 mol%)
1 h
This report
3
a
b
L represents the ligand used in respective reference
Tetrahydrofuran
Conclusion

This is the first report where 4,6-O-ethylidene--D-glucopyranosylamine derived ligand has
been screened for interactions with lanthanides. Based on the interaction results, synthesis of
glycoconnjugate derived Yb(III) complex has been executed and further the product has been
used as catalyst in Biginelli reaction. Totally twenty-one 3,4-dihydropyrimidin-2-(1H)-
ones/thiones derivative have been synthesised and the stability of catalyst has been
established via five times recycling process. After optimisation, we have performed the
catalytic reaction under neat condition with 1 mol% catalyst loading, and synthetic protocol
aligns with the green synthesis.
Declaration of competing interest
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
Acknowledgements
A. K. Sah is grateful to the Counsil of Scientific & Industrial Research (CSIR) for the financial
support under the Major Research Project (01(2918)/18/EMR-II) and SAIF/CRNTS, IIT
Bombay for providing CHNS/O analytical facility. We are also thankful to DST FIST and UGC
SAP for their financial support in procuring the instruments and developing the research
infrastructure.
Appendix A. Supplementary material
Supplementary data to this article can be found online at XXXXXXXXXX.

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Synthesis and Catalytic Application of D-Glucose Derived Ytterbium(III)
Complex in Biginelli Reaction
Vimal Kumar Madduluri, Santosh Kumar Mishra, Ajay K. Sah*

Highlights




First report on lanthanides interaction with glucopyranosylamine derivative
Application of N-glycoconjugate derived Yb(III) complex in Biginelli reaction
Neat synthesis of twenty-one 3,4-dihydropyrimidin-2(1H)-ones/thiones
Catalyst has been recycled for five times without appreciable loss in activity

Declaration of interests
☒
The authors declare that they have no known competing financial interests or personal
relationships that could have appeared to influence the work reported in this paper.
☐
The authors declare the following financial interests/personal relationships which may be
considered as potential competing interests:
Not required..

CRediT author statement
Vimal Kumar Madduluri: Conceptualization, Methodology, Investigation, Data curation,
Writing - Original Draft
Santosh Kumar Mishra: Formal analysis, Investigation, Data curation
Ajay K. Sah: Validation, Writing - Review & Editing, Supervision, Project administration