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Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water
Accepted Manuscript Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic Brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water Shila Darvishzad, Nader Daneshvar, Farhad Shirini, Hassan Tajik PII:
S0022-2860(18)31244-4
DOI:
https://doi.org/10.1016/j.molstruc.2018.10.053
Reference:
MOLSTR 25782
To appear in:
Journal of Molecular Structure
Received Date: 18 August 2018 Revised Date:
13 October 2018
Accepted Date: 17 October 2018
Please cite this article as: S. Darvishzad, N. Daneshvar, F. Shirini, H. Tajik, Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic Brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water, Journal of Molecular Structure (2018), doi: https://doi.org/10.1016/j.molstruc.2018.10.053. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic Brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water
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Shila Darvishzad,a Nader Daneshvar,b Farhad Shirini,a, b* Hassan Tajik a, b*
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Department of Chemistry, College of Science, University of Guilan, Rasht, Iran, 41335-19141, Tel/Fax: +981313233262; e-mail: [email protected] ([email protected]), [email protected] b Department of Chemistry, University Campus 2, University of Guilan, Rasht, Iran. Email: [email protected]
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Abstract— A new piperazine-based dicationic Brönsted acidic ionic salt named as piperazine-1,4-diium dihydrogen phosphate was prepared. After characterization by FT-IR, Mass and NMR spectroscopy, it was used as an efficient and reusable catalyst for the synthesis of 5‐arylidenepyrimidine‐2,4,6(1H,3H,5H)‐trione and pyrano[2,3‐d]pyrimidinone (thione) derivatives. Some of the advantages of this method are utilization of low amount of the catalyst, ease of work-up, short reaction times, excellent yields and acceptable reusability of the catalyst.
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Keywords: Dicationic Brönsted acidic ionic salt, piperazine-1,4-diium dihydrogen phosphate, 5-arylidene barbituric acids, pyrano[2,3-d] pyrimidinones, water-mediated reaction.
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1. Introduction
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Ionic liquids were introduced since the early of last century, but their applications were limited to the electrochemical field.
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Gradually, with the identification of their beneficial properties, such as non-flammable, recyclable, low vapor pressure, high
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thermal and chemical stability and the ability to dissolve the wide range of organic compounds, the domain of their applications
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became broader. Today, they are used in various industries as the solvents, catalysts, absorbents, ion exchangers, battery
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electrolytes and stationary phases in chromatography. Especially, with the rise of the green chemistry, the use of ionic liquids and
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green chemistry concepts merged in the field of development of chemical reactions. Today, one of the most important challenges
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for organic chemistry researchers is to reach green and environmentally friendly processes in organic synthesis [1-3].
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Dicationic ionic liquids (DILs) are those with two cations and anions in the structure. They can be as homoanonic and heteroanonic
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DILs [4]. DILs have higher thermal stability and selectivity in comparison with mono-cationic ones [5]. They have been used in
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many fields such as catalysis [6], solar cells [7], lubricants [8], fuel cells [9] and batteries [10].
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Utilization of ionic liquids as solvents sometimes is not affordable. In new point of view, another uses of ionic liquids are under
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attention. For example, Task specific ionic liquids (TSILs) is a term that refers to non-solvent usage of ionic liquids for catalysis of
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reactions and or for the separation of metals and gasses [11-12]. The concept of TSIL can be explained as the ability to design ionic
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liquid and to achieve the desired properties for a specific function [13].
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Piperazine is a heterocyclic nucleus which consists of a six-membered ring containing two nitrogen atoms at opposite positions in
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the ring. Piperazine derivatives are used in the preparation of various drugs, including: antimicrobial, anti-tubercular, antipsychotic,
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anticonvulsant, antidepressant, anti-inflammatory, cytotoxic, antimalarial, antiarrhythmic, antioxidant and antiviral drugs [14-16].
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In human and veterinary medicine, citrate, tartrate and phosphate salts of piperazine are used in the treatment of parasitic infections.
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ACCEPTED MANUSCRIPT The reported side effects of piperazine in humans are limited to allergic effects and there is no evidence of acute toxicity of
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piperazine in humans [17].
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The Knoevenagel condensation of aldehydes with active methylene compounds is a specific type of aldole condensation reaction,
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which involves the nucleophilic addition of an active hydrogen compound to a carbonyl group. This condensation is a significant
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and practical reaction for the carbon–carbon bond formation in organic synthesis [18].
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Barbituric acid, in the aqueous medium, as a strong acid, can be involved in the Knoevenagel condensation with various aldehydes.
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Barbituric acid and its derivatives are widely used in the pharmaceutical industry as sedative, hypnotic, antispasmodic, local
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anaesthetic [19] anticancer [20] anticonvulsant [21], complex and salt forming reagent [22-26 ]. Arylidene barbituric acids and their
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thio analogues have different industrial and laboratory applications more importantly as intermediates in the synthesis of
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heterocyclic compounds [27], benzyl barbituric derivatives [28], oxadiazaflavines [29] and unsymmetrical disulphides [30].
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Although in some cases this reaction is reported catalyst-free [31-33] but a number of reported catalysts for the preparation of these
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derivatives such as sulfonic acid functionalized nanoporous silica (SBA-Pr-SO3H) [34], BF3/nano γ-Al2O3 [35], Copper oxide
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Nanoparticles (CuO-NPs) [36], 2-Amino-3-(4-hydroxyphenyl) propanoic acid (L-tyrosine) [37], CoFeO4 nanoparticles [38],
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aminosulfonic acid (NH2SO3H) [39], Polyvinyl pyrrolidone stabilized nickel nanoparticles (PVP-Ni-Nps) [40], 1‐n‐butyl‐3‐
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methylimmidazolium tetrafluoroborate ([bmim]BF4) [41], Ethylenediammonium diacetate (EAN) [42], Cetyltrimethyl ammonium
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bromide (CTMAB) [43], sodium acetate (CH3COONa) [44], Ce1MgxZr1-xO2 (CMZO) [45] and ZrO2/SO42- [46].
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The three component reaction between an aldehyde, barbituric acid and malononitrile, eventuates to the synthesis of products called
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pirano[2,3-d] pyrimidineone derivatives. These heterocyclic compounds are highly regarded. They are used as antitumor [47],
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antibacterial [48], vasodilator, bronchiodilator [49], anti-allergic, anti-inflammatory, anti-asthma [50], antimalarial [51], antifungal
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[52] and herbicides [53]. Agents the diverse biological properties and therapeutic applications of these heterocyclic compounds
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justify their need for production. A number of reported methods for the preparation of these derivatives are included by use of
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microwave irradiation [54], ultrasonic irradiation [55], nano-SBA-Pr-SO3H [56], Al-HMS-20 [57], CaHPO4 [58], choline
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chloride.ZnCl2 [59], Zn[L-proline]2 [60], Boric acid and nano-titania sulfuric acid [61], ZnO-supported copper oxide (ZnO@CuO)
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[62] and [nano-Fe3O4@SiO2@(CH2)3-1-methylimidazole]HSO4 [63] as accelerators.
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2. Experimental
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2.1. Materials
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All chemicals were purchased from Merck or Fluka and Aldrich Chemical Companies. Yields refer to the isolated products.
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Products were characterized by their physical constants, comparison with authentic samples and FT-IR and NMR spectroscopy. The
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purity determination of the substrates and reaction progress were determined by thin layer chromatography (TLC).
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2.2. Instrumentation
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ACCEPTED MANUSCRIPT Melting points were measured by a Buchi B-545 apparatus in open capillary tubes. FT-IR spectra were recorded on a Perkin- Elmer
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spectrum BX series. The ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) were run on a Bruker 500 MHz spectrometer and 31P NMR
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(162 MHz) were obtained by a Bruker 400 MHz instrument in D2O solvent.
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2.3. Preparation of piperazine-1,4-diium dihydrogen phosphate ([H2-pip][H2PO4]2)
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In a 100 mL round-bottomed flask in an ice bath, piperazine (10.0 mmol, 1.94 g) was stirred in 40.0 mL dry dichloromethane. Then,
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an excess amount of phosphoric acid (2.0 mL) was added drop-wise to it during 10 minutes. After completion of the addition, the
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mixture was stirred for additional 24 h. Then, the solvent was decanted and the obtained white solid was washed with diethyl ether
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(3x30 mL) and ethanol (2x20 mL). Finally, the solid was completely dried using a rotary system and the desired piperazine-1,4-
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diium dihydrogen phosphate was obtained in 91% yield (Scheme 1).
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The characterization of the obtained ionic salt was determined using, mass, FT-IR, ¹H NMR and ¹³C NMR spectroscopic techniques
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and also by comparison of the melting points of piperazine and the obtained ionic salt.
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Spectral and physical data of piperazine-1,4-diium dihydrogen phosphate: M.P: 245 °C Dec.; FT-IR (KBr, cm-1) ߭max: 3247, 2862,
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2489, 1727, 1666, 1633, 1494, 1461, 1302, 1206, 1116, 1076, 963, 888, 604, 548, 499; 1H NMR (500 MHz, D2O) ߜ (ppm): 3.56-
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3.60 (m, 8H, 4xCH2); 13C NMR (125 MHz, D2O) ߜ (ppm): 40.2. 31P NMR (162 MHz, D2O) ߜ (ppm): -0.029.
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2.4. General procedure for the preparation of 5-arylidine barbituric and thiobarbituric acids
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In a 50 mL round-bottomed flask a mixture of aldehyde (5.0 mmol), (thio) barbituric acid (5.0 mmol) and [H2-pip][H2PO4]2 (70.0
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mg) in water/EtOH (25 mL, 1:1) was stirred and heated in an oil bath (80 °C). The completion of the reaction was monitored by
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TLC [n-hexane:ethylacetate:EtOH (7:3:1)]. After that, the product was separated by filtration and washed several times with water
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and EtOH. Finally, the product was dried at 50 °C and characterized by its spectral data and comparison with authentic samples.
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2.5. General procedure for the preparation of pyrano[2,3-d]pyrimidinedione derivatives
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In a 50 mL round-bottomed flask a mixture of aldehyde (5.0 mmol), (thio) barbituric acid (5.0 mmol), malononitrile, (5.5 mmol)
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and [H2-pip][H2PO4]2 (70.0 mg) in water/EtOH (25 mL, 1:1) was stirred and heated in an oil bath (80 °C). The completion of the
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reaction was monitored by TLC [n-hexane:ethylacetate:EtOH (7:3:1)]. After that, the product was separated by filtration and
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washed several times with water and few drops of EtOH. Finally, the product was dried at 50 °C and characterized by its spectral
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data and comparison with authentic samples.
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3. Results and discussion
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In recent years, introduction of new catalysts for organic transformations has been an important part of our research program[64-
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69]. In this regard, and because of its simplicity and cheapness, the preparation and use of ionic liquids based on piperazine as
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catalysts attracted our attention. Herein, in continuation of these studies, we introduce a new ionic salt based on piperazine,
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formulated as [H2-pip][H2PO4]2 which is efficiently able to catalyze the preparation of bioactive derivatives of (thio) barbituric
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acids. The structure of this ionic salt is proved by different techniques including FT-IR, 1H NMR,
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spectroscopies and its physical data, as described in the following sections.
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It should be mentioned that the preparation of [H2-pip][H2PO4]2 is previously reported using different method while only its
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crystallographic structure is investigated. Besides, the characterizations and elucidation of its structure as an organic-based
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compound is imperfect and not good enough. Also, there is no reference of catalytic ability for [H2-pip][H2PO4]2 in the published
C NMR,
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P NMR, mass
papers [70].
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3.1. Characterization of the catalyst
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After preparation of the [H2-pip][H2PO4]2, various spectroscopic techniques were used to characterize the structure of the
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compound. Here is some elucidations in detail:
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3.1.1. FT-IR analysis
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In the FT-IR spectra of [H2-pip][H2PO4]2, the broadening in the area of 2500-3300 cm-1 is attributed to acidic N-H and O-H
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stretching vibrations. Medium peaks in the area of 2550-2700 cm-1 are due to (O=) P-OH vibrations. Also, appearance of a bunch of
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peaks in the range of 800-1200 cm-1 known for compounds containing phosphoric acid derivatives is observed. (1116 cm-1 and 1076
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cm-1 for P=O; 1019 cm-1 and 963 cm-1 for P-O vibrations). Peaks at 604 cm-1 and 548 cm-1 are due to O=P-O vibrations (Figure 1).
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3.1.2. NMR spectroscopy
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In the 1H NMR spectra of [H2-pip][H2PO4]2, eight hydrogens related to the piperazinium ring are observed in the chemical shift of
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3.56-3.60 ppm as a multiplete peak. Also, a peak related to little impurity of coagulated raw piperazine (3.78 %) is observed as
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multiplete in the range of 2.69-2.73 ppm (Figure 2).
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In the case of 13C NMR, one peak at 40.2 ppm is observed which is related to the symmetric carbons of piperazinium ring (Figure
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3).
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It should be mentioned that, since this ionic compound is only soluble in water and for this reason D2O was selected as the solvent
116
of NMR, and, for this reason, the acidic protons of NH or OH did not appear in the 1H NMR spectra, but, in comparison with the 1H
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NMR of piperazine, a noticeable chemical shift of the hydrogens of the ring in its ionic form (due to change of electronegativity of
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the nitrogens and ionic environment) is well observed for both of the 1H NMR and 13C NMR spectra.
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In the 31P NMR spectra of [H2-pip][H2PO4] as a symmetrical compound, one peak at the -0.029 ppm is observed which is related
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to the phosphorus of dihydrogen phosphate anion (Figure 4). This single peak proved that the structure is symmetrical and also
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proves the presence of H2PO4 anion in the structure which was not observable in 1H NMR using D2O as the solvent.
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3.1.3. Mass spectroscopy
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weight of the catalyst. Also, other peaks related to the other fragmentations can be seen in this spectrum (Figure 5).
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3.2. Catalytic activity
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3.2.1. Optimizations and derivations
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On the basis of the obtained structural information, we predicted that [H2-pip][H2PO4]2 can be used as an efficient catalyst to
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promote the reactions needing acidic catalysts to speed-up. So, we were interested to investigate the performance of this catalyst in
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the acceleration of the synthesis of 5-arylidene (thio) barbituric acids and pyrano [2,3-d] pyrimidinone (thiones) derivatives. For the
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optimization of the reaction conditions, the effect of different factors including the catalyst loading, temperature, and solvent in the
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preparation of 4-chlorobenzaldehyde derivatives of both of the requested target molecules was studied.
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3.2.1. Optimization step for the preparation of 5-arylidene (thio)barbituric acid derivatives in the presence of [H2-pip][H2PO4]2
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Preforming the reaction in the absence of the catalyst and solvent did not led to noticeable product. Also, the reaction in the absence
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of solvent even with catalyst couldn’t provide the product. In the same way, no significant product was observed when the mixture
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of the reaction was refluxed in chloroform. Refluxing of the mixture of the reaction in acetonitrole resulted in some product, but the
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reaction was not completed, as like as heating in pure water at 50°C. The reaction led to the product in refluxing water, ethanol or a
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mixture of them, but the best results were obtained when the reaction is perfoemed in the mixture of water/ethanol (1:1) at 80°C.
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Also, the optimum amounts of the catalyst is determind as 5 mol% (Tables 1 and 2).
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After optimization and determination of the best conditions for both reactions, various types of aldehydes containing electron-
140
donating or electron-withdrawing groups and heterocylic aldehydes were subjected to the mentioned reactions. All of them reacted
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well in the reaction to give their corresponding products in high yields during short reaction times. No significant difference for the
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substituent effect was observed in comparison but in the case of thiobarbituric acid derivatives, the rates and yields of the reactions
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were ralatively lower than the reaction of barbituric acid derivatives (Tables 3 and 4).
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3.2.2. Reusability of the catalyst
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In order to show the reusability potential of the catalyst, the synthesis of compounds 1e and 2e was studied again. In these studies
146
and after the completion of the reaction, the product was isolated by filtration and the same reaction repeated in the filtrated solution
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without addition of extra amounts of the catalyst. The results show that this catalyst can be reused for four times in both of the
148
mentioned reactions without significant loss of its catalytic activity (Figures 6 and 7).
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3.2.3. Comparison of the catalitic ability
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In order to show the catalytic ability of [H2-pip][H2PO4]2, the resuls related to preparation of compounds 1e and 2e are compared
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with the same results obtained using other catalysts. In all cases, the introduced catalyst had one or more advantages from the
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made the catalyst relatively green in comparison to some other ones (Tables 5 and 6).
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3.3. Mechanistic study
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The proposed mechanism for the mentioned reactions is shown in Scheme 3. On the basis of this scheme, the catalyst enolized
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(thio)barbituric acid attacks to the aldehyde which is also activated by the acidic proton of the catalyst. After elimination of water
157
molecule, 5-arylidene (thio)barbituric acid derivative is achieved.
158
In the case of pyrano[2,3-d]pyrimidinone (thione) products, the produced 5-arylidene (thio)barbituric acid is attacked by a molecule
159
of malononitrile which is activated by the catalyst. After a keto-enol tautomerization, cyclization occurs by nucleophilic attack of
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the hydroxyl group to the activated nitrile group. At the end, with imine-enamin tautomerization, the expected products can be
161
obtained (Scheme 3).
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4. Conclusion
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In this study, we prepared a new acidic ionic salt by simple addition of phosphoric acid to piperazine and investigate its catalytic
164
activity in the synthesis of 5‐arylidenepyrimidine‐2,4,6(1H,3H,5H)‐trione and pyrano[2,3‐d]pyrimidinone derivatives. The
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introduced catalyst has the advantages of similar Bronested ionic liquids, including the ability of being recover, high thermal
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stability and non-hygroscopic nature which causes it to be stocked to store and use for a long time. Also, it is very suitable to be
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used in humid climates.
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Acknowledgments
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We are thankful to the Research Council of the University of Guilan for the partial support of this research.
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[47] a) E. M. Griva, S. Lee, C. W. Siyal, D. S. Duch, C. A. Nichol, J. Med. Chem. 23 (1980) 327-329; b) G. L. Anderson, J. L. Shim, A. D. Broom, J. Org. Chem. 41 (1976) 1095-1099. [48] M. M. Ghorab, A. Y. Hassan, Phosphorus, Sulfur Silicon Relat. Elem. 14 (1998) 251-261. [49] a) S. Furuja, T. Ohtaki, Chem. Abstr. 121 (1994): 205395w. Eur Pat Appl EP, 608565.; b) D. Heber, C. Heers, U. Ravens, Die Pharmazie, 48 (1993) 537-541. [50] N. Kitamura, A. Onishi, Eur. Pat., 163599, 1984, Chem. Abstr. 104 (1984) 186439. [51] J. Davoll, J. Clarke, E.F. Eislager. J. Med. Chem., 15 (1972) 837. [52] V. K. Ahluwalia, R. Kumar, K. Khurana, R. Batla. Tetrahedron 46 (1990) 3953-3962. [53] G. Levitt, US Pat., 4339267, 1982, Chem. Abstr. 98 (1983) 215602g. [54] (a) I. Devi, B. S. D. Kumar, P. J. Bhuyan, Tetrahedron Lett. 44 (2003) 8307–8310. (b) Y. Gao, S. Tu, T. Li, X. Zhang, S. Zhu, F. Fang, D. Shi, Synth. Commun. 34 (2004) 1295–1299.
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[55] T. S. Jin, L. B. Liu, Y. Zhao, T. S. Li, J. Chem. Res. 3 (2005) 162–163.
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[67] F. Shirini, M. S. N. Langarudi, N. Daneshvar, N. Jamasbi, rankhah-Khanghah, J. Mol. Struct. 1161 (2018) 366-382.
[56] G. M. Ziarani, S. Faramarzi, S. Asadi, A. Badiei, R. Bazl, M. Amanlou, DARU J. Pharm. Sci 21 (2013) 1-13. [57] B. Sabour, M. H. Peyrovi, M. Hajimohammadi, Res. Chem. Intermed. 41 (2015) 1343-1350. [58] M. A. Bodaghifard, M. Solimannenejad, S. Asadbegi, S. Dolatabadifarahni, Res. Chem. Intermed. 42 (2016) 1165-1179. [59] D. K. Yadav, M. A. Quraishi, J. Mater. Environ. Sci. 5 (2014) 1075-1078. [60] A. Khazaei, H. A. A. Nik, A. R. Moosavi-Zare, J. Chin. Chem. Soc. 62 (2015) 675-679. [61] J. Albadi, A. Mansournezhad, T. Sadeghi, Res. Chem. Intermed. 4 (2015) 8317-8326. (4or41)
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[62] M. M. Heravi, A. Ghods, Azadeh, K. Bakhtiari, F. Derikvand, Synth. Commun. 40 (2010) 1927-1931. [63] S. Sajjadifar, M. A. Zolfigol, F. Tami, Chin Chem Soc. (2018) doi:10.1002/jccs.201800171.
[64] N. Daneshvar, F. Shirini, M. S. N. Langarudi. ,R. Karimi-Chayjani, Bioorg. Chem. 77 (2018) 68-73. [65] F. Shirini, M. S. N. Langarudi, N. Daneshvar, J. Mol. Liq. 234 (2017) 268-278.
[66] M. Mashhadinezhad, F. Shirini, M. Mamaghani, Microporous Mesoporous Mater. 262 (2018) 269-282.
[69] N. Seyyedi, M. Safarpoor, F. Shirini, RSC Adv. 6 (2016) 44630-44640.
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[68] N. Daneshvar, M. Nasiri, M. Shirzad, M. S. N. Langarudi, F. Shirini, H. Tajik, New J. Chem. (2018).
(2007) 72-81.
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[70] T. R. Jensen, J. E. Jørgensen, R. G. Hazell, H. J. Jakobsen, M. A. Chevallier, L. Jørgensen, A. Wiedermann, Solid State Sciences, 9
[71] G. Thirupathi, M. Venkatanarayana, P. K. Dubey, Y. B. 8umara, Chem. Sci. Trans. 2 (2013) 441-446. [72] S. Mashkouri , M. R. Naimi-Jamal, Molecules 14 (2009) 474-479.
[73] H. Hosseini, E. Sheikhhosseini, D. Ghazanfari, Iran. J. Catal. 6 (2016) 121-125. [74] N. Montazeri. Int. J. Nano Dimens. 6 (2015) 283-287.
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[75] D. N. Chavan, D.R. Patil, D.R. Kumbhar, M.B. Deshmukh, Chem. Sci. Rev. Lett. 4 (2015) 1051–1058.
8
ACCEPTED MANUSCRIPT
Scheme. 1. Preparation of piperazine-1,4-diium dihydrogen phosphate.
RI PT
252 253
AC C
EP
TE D
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SC
254
9
255 256 257
AC C
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ACCEPTED MANUSCRIPT
Fig. 1 The FT-IR spectra of piperazine (a) and piperazine-1,4-diium dihydrogen phosphate (b).
10
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Fig. 2 The 1H NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
AC C
258 259
M AN U
SC
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11
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EP
263
Fig. 3 The 13C NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
AC C
261 262
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12
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266
Fig. 4 The 31P NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
AC C
264 265
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13
267 268
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Fig. 5 The mass spectrum of piperazine-1,4-diium dihydrogen phosphate.
EP
271
AC C
270
TE D
269
14
EP
TE D
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SC
Scheme 2. Synthesis of 5-arylidene barbituric acid and pyrano[2,3d]pyrimidinone derivatives using [H2-pip][H2PO4]2 under optimized conditions.
AC C
272 273 274 275 276
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ACCEPTED MANUSCRIPT
15
ACCEPTED MANUSCRIPT Table 1. Optimization of the reaction conditions for the preparation of 5-arylidene barbituric acid derivative of 4-chlorobenzaldehyde. Entry
Catalyst (mol%)
Solvent
Temperature (°C)
Time (min.)
Yield (%) (isolated)
1
-
-
80-100
100
trace*
2
5
-
80-100
100
trace*
3
5
CHCl3
Reflux
100
trace*
5
CH3CN
Reflux
100
60
5
H₂O
50
65
68
6
5
H₂O
80
40
7
5
H2O
Reflux
35
8
5
EtOH
Reflux
50
9
3.5
H₂O/EtOH (1:1)
80
35
10
5
H₂O/EtOH (1:1)
80
20
11
6.4
H₂O/EtOH (1:1)
80
12
5
H₂O/EtOH (2:1)
80
RI PT
4 5
81
84
72
83 96
SC
277 278
20
86
38
88
* Reaction was not completed.
280 281 282
Table 2. Optimization of the reaction conditions for the preparation of pyrano[2,3-d] pyrimidinone derivative of 4-chlorobenzaldehyde. Catalyst (mol%)
Solvent
1
-
-
2
5
-
3
5
CHCl3
4
5
5
5
6
5
7
5
8
5
283 284
Yield (%) (isolated)
80-100
120
Trace*
80-100
120
Trace*
Reflux
120
Trace*
CH3CN
Reflux
120
Mixture
EtOH
Reflux
45
72
H₂O
50
65
68
H₂O
80
40
81
H2O
Reflux
30
84
3.5
H₂O/EtOH (1:1)
50
35
83
5
H₂O/EtOH (1:1)
80
24
95
AC C
10
Time (min)
EP
9
Temperature (°C)
TE D
Entry
M AN U
279
11
6.4
H₂O/EtOH (1:1)
Reflux
20
92
12
5
H₂O/EtOH (2:1)
80
40
87
* Reaction was not completed.
16
EP
TE D
Scheme 3. The plausible mechanisms of the studied reactions in the presence of [H2-pip][H2PO4]2.
AC C
285 286 287
M AN U
SC
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ACCEPTED MANUSCRIPT
17
ACCEPTED MANUSCRIPT 96
24
22
89
26 Yield(%) Time(min)
Time(min)
1 20
2 22
3 24
4 26
Yield(%)
96
94
91
89
SC
Fig. 6 Reusability of the catalysts in the preparation of 5-arylidene barbituric acid derivative of 4-chlorobenzaldehyde.
95 100 80 60 40
24
93
90
29
26
TE D
20
M AN U
288 289 290 291 292 293 294
20
91
RI PT
100 80 60 40 20 0
94
87
32
Yield (%) Time (min)
0
298
3 29
4 32
Yield (%)
95
93
90
87
EP
296 297
2 26
Fig. 7 Reusability of the catalysts in the preparation of pyrano[2,3-d]pyrimidinone derivative of 4- chlorobenzaldehyde .
AC C
295
Time (min)
1 24
18
ACCEPTED MANUSCRIPT Table 3. Synthesis of different derivatives of 5-arylidene barbituric acids. X
Symbol
Time (min.)
Yield (%)
1
C6H5CHO
O
1a
35
74
249-251
249-252 [68]
2
4-FC6H4CHO
O
1b
30
87
>300
>300 [68]
3
2-ClC6H4CHO
O
1c
25
92
250-252
249-251 [68]
4
3-ClC6H4CHO
O
1d
30
90
274–276
275–277 [68]
5
4-ClC6H4CHO
O
1e
20
96
>300
298-300 [68]
6
4-BrC6H4CHO
O
1f
30
95
292-294
292-294 [68]
7
2-NO₂C6H4CHO
O
1g
20
91
272-274
271-273 [68]
8
3-NO₂C6H4CHO
O
1h
28
90
226–228
226–228 [68]
9
4-NO₂C6H4CHO
O
1i
22
93
270–272
268–270 [66]
10
4-OHC6H4CHO
O
1j
20
90
>300
>300 [68]
11
2-OCH₃C6H4CHO
O
12
3-OCH₃C6H4CHO
O
13
4-OCH₃C6H4CHO
O
14
4-CH₃C6H4CHO
O
15
Terephthalaldehyde
O
16
Cinnamaldehyde
O
17
Furfural
18 19
21
SC
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85
270-272
270-271 [68]
1l
45
88
225-227
227-230[35]
1m
35
89
295-297
294-297 [68]
1n
30
94
278-280
277-280 [68]
1o
15
90
>300
>300 [68]
1p
20
89
267-269
267-268 [68]
O
1q
15
87
258-260
258-260 [66]
4-FC6H4CHO
S
1r
30
91
214-216
218-219 [71]
4-ClC6H4CHO
S
1s
25
90
287–290
287–290 [69]
2-NO₂C6H4CHO
S
1t
30
87
248-250
246-250 [69]
3-NO₂C6H4CHO
S
1u
35
85
266-268
266-268 [69]
TE D
1k
AC C
a
RI PT
Aldehyde
20
300 301 302
m.p. (°C) Reported Observed [ref.]
Entry
EP
299
Isolated yields.
19
ACCEPTED MANUSCRIPT Table 4. Synthesis of different derivatives of pyrano[2,3,d] pyrimidinone(thione) derivatives. Entry
Symbol
Time (min.)
Yield (%)
m.p. (°C) Observed
Reported [ref.]
O
2a
13
79
205-207
206-209 [72]
2
4-FC6H4CHO
O
2b
20
93
258-260
256-260 [69]
3
2-ClC6H4CHO
O
2c
20
92
214-216
212-215 [72]
4
3-ClC6H4CHO
O
2d
25
93
242-243
241-243 [68]
5
4-ClC6H4CHO
O
2e
24
95
238-240
237-240 [69]
6
4-BrC6H4CHO
O
2f
35
95
229-231
229-231 [69]
7
2-NO₂C6H4CHO
O
2g
24
86
255-258
256-258 [66]
8
3-NO₂C6H4CHO
O
2h
25
90
268-270
269-270 [66]
9
4-NO₂C6H4CHO
O
2i
30
89
237-238
237-239 [66]
10
4-OHC6H4CHO
O
11
2-OCH₃C6H4CHO
O
12
3-OCH₃C6H4CHO
O
13
4-OCH₃C6H4CHO
O
14
4-CH₃C6H4CHO
O
15
Terephthalaldehyde
16
M AN U
SC
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C6H5CHO
30
70
>300
>300 [66]
2k
30
81
220-222
221-222 [29]
2l
30
86
236-237
236-237 [66]
2m
30
90
281-282
280-284[68]
2n
45
88
225-227
223-225 [68]
O
2o
25
93
>300
>300 [68]
Furfural
O
2p
45
82
280-281
281-282 [57]
17
4-ClC6H4CHO
S
2q
40
91
>300
>300 [69]
18
3-NO₂C6H4CHO
S
2r
50
85
234-236
234-235[69]
S
2s
40
78
233-235
234-235[69]
TE D
2j
4-NO₂C6H4CHO
Isolated yields.
AC C
a
X
1
19
304
Aldehyde
EP
303
20
ACCEPTED MANUSCRIPT
Catalyst
Amount of catalyst
Conditions
Time (min.)
Yield (%)
Ref.
1
BF3/nano-γ-Al2O3
60 mg
Ethanol, R.T.
30
84
[35]
2
NH2SO3H
100 mol%
Grinding-laying
180
93
[39]
3
PVP-Ni Nps
100 mg
Ethylene glycol, 50 °C
10-15
93
[40]
4
[bmim]BF4
0.2 mL
Grinding-laying
5
EAN
2 mL
R.T.
6
CTMAB
50 mol%
H2O, R.T.
7
CH3COONa
100 mol%
Grinding
8
CMZO
200 mg
EtOH, 60-70 °C
9
p-Dodecylbenzene sulfonic acid (DBSA)
30 mol%
H2O, reflux
10
[H2-pip][H2PO4]2
5 mol%
RI PT
Entry
78
[41]
180
83
[42]
30
82
[43]
10
91
[44]
60
85
[45]
67
62
[73]
20
96
This work
M AN U
SC
120
H2O/EtOH (1:1) 80°C
Table 6. Comparison of catalytic activity of [H2-pip][H2PO4]2 with some reported catalysts in the
synthesis of 4-chlorophenyl derivative of pyrano[2,3,d] pyrimidinone. Amount of catalyst
Conditions
Time (min.)
Yield (%)
Ref.
1
Al-HMS-20
30 mg
EtOH, R.T.
720
92
[57]
2
[BMIm]BF4
30 mg
90 °C, S.F.
180
92
[41]
3
CaHPO4
10 mol%
H2O/EtOH (4:1)
120
92
[58]
4
Choline chloride.ZnCl2
50 mol%
EtOH, 75 °C
120
94
[59]
5
Boric acid
10 mol%
110
85
[61]
6
Nano-titania sulfuric acid
20 mg
60
89
[61]
TE D
Entry
Catalyst
AC C
307 308 309 310
Table 5. Comparison of catalytic activity of [H2-pip][H2PO4]2 with some reported catalysts in the synthesis of 4-chlorophenyl derivative of 5-arylidene barbituric acid.
EP
305 306
THF/H2O (4:1), Reflux EtOH/H2O (19:1), Reflux
7
Zn[L-proline]2
17 mol%
EtOH, Reflux
50
90
[60]
8
ZnO@CuO
30 mg
H2O, Reflux
12
91
[62]
9
SBA-Pr-SO3H
20 mg
S.F., 140 °C
45
30
[56]
10
nano Al2O3
20 mol%
H2O: EtOH,reflux
4h
87
[74]
11
Trichloroisocyanur ic acid
10 mol%
H2O, Reflux
90
93
[75]
12
[H2-pip][H2PO4]2
5 mol%
H2O/EtOH (1:1) 80°C
24
95
This work
311
21
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ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights Synthesis, characterization and utilization of an ionic salt base on piperazine.
•
Use of environmentally friendly and nontoxic phosphoric acid for the catalyst.
•
Various spectroscopic characterization including FT-IR, 1H NMR, 13C NMR and 31P
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•
NMR.
High product yields and rates of the reaction and good reusability of the catalyst.
•
Preforming the reaction in green media.
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S0022-2860(18)31244-4
DOI:
https://doi.org/10.1016/j.molstruc.2018.10.053
Reference:
MOLSTR 25782
To appear in:
Journal of Molecular Structure
Received Date: 18 August 2018 Revised Date:
13 October 2018
Accepted Date: 17 October 2018
Please cite this article as: S. Darvishzad, N. Daneshvar, F. Shirini, H. Tajik, Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic Brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water, Journal of Molecular Structure (2018), doi: https://doi.org/10.1016/j.molstruc.2018.10.053. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT
3
Introduction of piperazine-1,4-diium dihydrogen phosphate as a new and highly efficient dicationic Brönsted acidic ionic salt for the synthesis of (thio)barbituric acid derivatives in water
4
Shila Darvishzad,a Nader Daneshvar,b Farhad Shirini,a, b* Hassan Tajik a, b*
2
5 6 7 8
a
Department of Chemistry, College of Science, University of Guilan, Rasht, Iran, 41335-19141, Tel/Fax: +981313233262; e-mail: [email protected] ([email protected]), [email protected] b Department of Chemistry, University Campus 2, University of Guilan, Rasht, Iran. Email: [email protected]
RI PT
1
Abstract— A new piperazine-based dicationic Brönsted acidic ionic salt named as piperazine-1,4-diium dihydrogen phosphate was prepared. After characterization by FT-IR, Mass and NMR spectroscopy, it was used as an efficient and reusable catalyst for the synthesis of 5‐arylidenepyrimidine‐2,4,6(1H,3H,5H)‐trione and pyrano[2,3‐d]pyrimidinone (thione) derivatives. Some of the advantages of this method are utilization of low amount of the catalyst, ease of work-up, short reaction times, excellent yields and acceptable reusability of the catalyst.
14 15
Keywords: Dicationic Brönsted acidic ionic salt, piperazine-1,4-diium dihydrogen phosphate, 5-arylidene barbituric acids, pyrano[2,3-d] pyrimidinones, water-mediated reaction.
16
1. Introduction
17
Ionic liquids were introduced since the early of last century, but their applications were limited to the electrochemical field.
18
Gradually, with the identification of their beneficial properties, such as non-flammable, recyclable, low vapor pressure, high
19
thermal and chemical stability and the ability to dissolve the wide range of organic compounds, the domain of their applications
20
became broader. Today, they are used in various industries as the solvents, catalysts, absorbents, ion exchangers, battery
21
electrolytes and stationary phases in chromatography. Especially, with the rise of the green chemistry, the use of ionic liquids and
22
green chemistry concepts merged in the field of development of chemical reactions. Today, one of the most important challenges
23
for organic chemistry researchers is to reach green and environmentally friendly processes in organic synthesis [1-3].
24
Dicationic ionic liquids (DILs) are those with two cations and anions in the structure. They can be as homoanonic and heteroanonic
25
DILs [4]. DILs have higher thermal stability and selectivity in comparison with mono-cationic ones [5]. They have been used in
26
many fields such as catalysis [6], solar cells [7], lubricants [8], fuel cells [9] and batteries [10].
27
Utilization of ionic liquids as solvents sometimes is not affordable. In new point of view, another uses of ionic liquids are under
28
attention. For example, Task specific ionic liquids (TSILs) is a term that refers to non-solvent usage of ionic liquids for catalysis of
29
reactions and or for the separation of metals and gasses [11-12]. The concept of TSIL can be explained as the ability to design ionic
30
liquid and to achieve the desired properties for a specific function [13].
31
Piperazine is a heterocyclic nucleus which consists of a six-membered ring containing two nitrogen atoms at opposite positions in
32
the ring. Piperazine derivatives are used in the preparation of various drugs, including: antimicrobial, anti-tubercular, antipsychotic,
33
anticonvulsant, antidepressant, anti-inflammatory, cytotoxic, antimalarial, antiarrhythmic, antioxidant and antiviral drugs [14-16].
34
In human and veterinary medicine, citrate, tartrate and phosphate salts of piperazine are used in the treatment of parasitic infections.
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1
ACCEPTED MANUSCRIPT The reported side effects of piperazine in humans are limited to allergic effects and there is no evidence of acute toxicity of
36
piperazine in humans [17].
37
The Knoevenagel condensation of aldehydes with active methylene compounds is a specific type of aldole condensation reaction,
38
which involves the nucleophilic addition of an active hydrogen compound to a carbonyl group. This condensation is a significant
39
and practical reaction for the carbon–carbon bond formation in organic synthesis [18].
40
Barbituric acid, in the aqueous medium, as a strong acid, can be involved in the Knoevenagel condensation with various aldehydes.
41
Barbituric acid and its derivatives are widely used in the pharmaceutical industry as sedative, hypnotic, antispasmodic, local
42
anaesthetic [19] anticancer [20] anticonvulsant [21], complex and salt forming reagent [22-26 ]. Arylidene barbituric acids and their
43
thio analogues have different industrial and laboratory applications more importantly as intermediates in the synthesis of
44
heterocyclic compounds [27], benzyl barbituric derivatives [28], oxadiazaflavines [29] and unsymmetrical disulphides [30].
45
Although in some cases this reaction is reported catalyst-free [31-33] but a number of reported catalysts for the preparation of these
46
derivatives such as sulfonic acid functionalized nanoporous silica (SBA-Pr-SO3H) [34], BF3/nano γ-Al2O3 [35], Copper oxide
47
Nanoparticles (CuO-NPs) [36], 2-Amino-3-(4-hydroxyphenyl) propanoic acid (L-tyrosine) [37], CoFeO4 nanoparticles [38],
48
aminosulfonic acid (NH2SO3H) [39], Polyvinyl pyrrolidone stabilized nickel nanoparticles (PVP-Ni-Nps) [40], 1‐n‐butyl‐3‐
49
methylimmidazolium tetrafluoroborate ([bmim]BF4) [41], Ethylenediammonium diacetate (EAN) [42], Cetyltrimethyl ammonium
50
bromide (CTMAB) [43], sodium acetate (CH3COONa) [44], Ce1MgxZr1-xO2 (CMZO) [45] and ZrO2/SO42- [46].
51
The three component reaction between an aldehyde, barbituric acid and malononitrile, eventuates to the synthesis of products called
52
pirano[2,3-d] pyrimidineone derivatives. These heterocyclic compounds are highly regarded. They are used as antitumor [47],
53
antibacterial [48], vasodilator, bronchiodilator [49], anti-allergic, anti-inflammatory, anti-asthma [50], antimalarial [51], antifungal
54
[52] and herbicides [53]. Agents the diverse biological properties and therapeutic applications of these heterocyclic compounds
55
justify their need for production. A number of reported methods for the preparation of these derivatives are included by use of
56
microwave irradiation [54], ultrasonic irradiation [55], nano-SBA-Pr-SO3H [56], Al-HMS-20 [57], CaHPO4 [58], choline
57
chloride.ZnCl2 [59], Zn[L-proline]2 [60], Boric acid and nano-titania sulfuric acid [61], ZnO-supported copper oxide (ZnO@CuO)
58
[62] and [nano-Fe3O4@SiO2@(CH2)3-1-methylimidazole]HSO4 [63] as accelerators.
59
2. Experimental
60
2.1. Materials
61
All chemicals were purchased from Merck or Fluka and Aldrich Chemical Companies. Yields refer to the isolated products.
62
Products were characterized by their physical constants, comparison with authentic samples and FT-IR and NMR spectroscopy. The
63
purity determination of the substrates and reaction progress were determined by thin layer chromatography (TLC).
64
2.2. Instrumentation
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spectrum BX series. The ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) were run on a Bruker 500 MHz spectrometer and 31P NMR
67
(162 MHz) were obtained by a Bruker 400 MHz instrument in D2O solvent.
68
2.3. Preparation of piperazine-1,4-diium dihydrogen phosphate ([H2-pip][H2PO4]2)
69
In a 100 mL round-bottomed flask in an ice bath, piperazine (10.0 mmol, 1.94 g) was stirred in 40.0 mL dry dichloromethane. Then,
70
an excess amount of phosphoric acid (2.0 mL) was added drop-wise to it during 10 minutes. After completion of the addition, the
71
mixture was stirred for additional 24 h. Then, the solvent was decanted and the obtained white solid was washed with diethyl ether
72
(3x30 mL) and ethanol (2x20 mL). Finally, the solid was completely dried using a rotary system and the desired piperazine-1,4-
73
diium dihydrogen phosphate was obtained in 91% yield (Scheme 1).
74
The characterization of the obtained ionic salt was determined using, mass, FT-IR, ¹H NMR and ¹³C NMR spectroscopic techniques
75
and also by comparison of the melting points of piperazine and the obtained ionic salt.
76
Spectral and physical data of piperazine-1,4-diium dihydrogen phosphate: M.P: 245 °C Dec.; FT-IR (KBr, cm-1) ߭max: 3247, 2862,
77
2489, 1727, 1666, 1633, 1494, 1461, 1302, 1206, 1116, 1076, 963, 888, 604, 548, 499; 1H NMR (500 MHz, D2O) ߜ (ppm): 3.56-
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3.60 (m, 8H, 4xCH2); 13C NMR (125 MHz, D2O) ߜ (ppm): 40.2. 31P NMR (162 MHz, D2O) ߜ (ppm): -0.029.
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2.4. General procedure for the preparation of 5-arylidine barbituric and thiobarbituric acids
80
In a 50 mL round-bottomed flask a mixture of aldehyde (5.0 mmol), (thio) barbituric acid (5.0 mmol) and [H2-pip][H2PO4]2 (70.0
81
mg) in water/EtOH (25 mL, 1:1) was stirred and heated in an oil bath (80 °C). The completion of the reaction was monitored by
82
TLC [n-hexane:ethylacetate:EtOH (7:3:1)]. After that, the product was separated by filtration and washed several times with water
83
and EtOH. Finally, the product was dried at 50 °C and characterized by its spectral data and comparison with authentic samples.
84
2.5. General procedure for the preparation of pyrano[2,3-d]pyrimidinedione derivatives
85
In a 50 mL round-bottomed flask a mixture of aldehyde (5.0 mmol), (thio) barbituric acid (5.0 mmol), malononitrile, (5.5 mmol)
86
and [H2-pip][H2PO4]2 (70.0 mg) in water/EtOH (25 mL, 1:1) was stirred and heated in an oil bath (80 °C). The completion of the
87
reaction was monitored by TLC [n-hexane:ethylacetate:EtOH (7:3:1)]. After that, the product was separated by filtration and
88
washed several times with water and few drops of EtOH. Finally, the product was dried at 50 °C and characterized by its spectral
89
data and comparison with authentic samples.
90
3. Results and discussion
91
In recent years, introduction of new catalysts for organic transformations has been an important part of our research program[64-
92
69]. In this regard, and because of its simplicity and cheapness, the preparation and use of ionic liquids based on piperazine as
93
catalysts attracted our attention. Herein, in continuation of these studies, we introduce a new ionic salt based on piperazine,
94
formulated as [H2-pip][H2PO4]2 which is efficiently able to catalyze the preparation of bioactive derivatives of (thio) barbituric
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acids. The structure of this ionic salt is proved by different techniques including FT-IR, 1H NMR,
13
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spectroscopies and its physical data, as described in the following sections.
97
It should be mentioned that the preparation of [H2-pip][H2PO4]2 is previously reported using different method while only its
98
crystallographic structure is investigated. Besides, the characterizations and elucidation of its structure as an organic-based
99
compound is imperfect and not good enough. Also, there is no reference of catalytic ability for [H2-pip][H2PO4]2 in the published
C NMR,
31
P NMR, mass
papers [70].
101
3.1. Characterization of the catalyst
102
After preparation of the [H2-pip][H2PO4]2, various spectroscopic techniques were used to characterize the structure of the
103
compound. Here is some elucidations in detail:
104
3.1.1. FT-IR analysis
105
In the FT-IR spectra of [H2-pip][H2PO4]2, the broadening in the area of 2500-3300 cm-1 is attributed to acidic N-H and O-H
106
stretching vibrations. Medium peaks in the area of 2550-2700 cm-1 are due to (O=) P-OH vibrations. Also, appearance of a bunch of
107
peaks in the range of 800-1200 cm-1 known for compounds containing phosphoric acid derivatives is observed. (1116 cm-1 and 1076
108
cm-1 for P=O; 1019 cm-1 and 963 cm-1 for P-O vibrations). Peaks at 604 cm-1 and 548 cm-1 are due to O=P-O vibrations (Figure 1).
109
3.1.2. NMR spectroscopy
110
In the 1H NMR spectra of [H2-pip][H2PO4]2, eight hydrogens related to the piperazinium ring are observed in the chemical shift of
111
3.56-3.60 ppm as a multiplete peak. Also, a peak related to little impurity of coagulated raw piperazine (3.78 %) is observed as
112
multiplete in the range of 2.69-2.73 ppm (Figure 2).
113
In the case of 13C NMR, one peak at 40.2 ppm is observed which is related to the symmetric carbons of piperazinium ring (Figure
114
3).
115
It should be mentioned that, since this ionic compound is only soluble in water and for this reason D2O was selected as the solvent
116
of NMR, and, for this reason, the acidic protons of NH or OH did not appear in the 1H NMR spectra, but, in comparison with the 1H
117
NMR of piperazine, a noticeable chemical shift of the hydrogens of the ring in its ionic form (due to change of electronegativity of
118
the nitrogens and ionic environment) is well observed for both of the 1H NMR and 13C NMR spectra.
119
In the 31P NMR spectra of [H2-pip][H2PO4] as a symmetrical compound, one peak at the -0.029 ppm is observed which is related
120
to the phosphorus of dihydrogen phosphate anion (Figure 4). This single peak proved that the structure is symmetrical and also
121
proves the presence of H2PO4 anion in the structure which was not observable in 1H NMR using D2O as the solvent.
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3.1.3. Mass spectroscopy
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124
weight of the catalyst. Also, other peaks related to the other fragmentations can be seen in this spectrum (Figure 5).
125
3.2. Catalytic activity
126
3.2.1. Optimizations and derivations
127
On the basis of the obtained structural information, we predicted that [H2-pip][H2PO4]2 can be used as an efficient catalyst to
128
promote the reactions needing acidic catalysts to speed-up. So, we were interested to investigate the performance of this catalyst in
129
the acceleration of the synthesis of 5-arylidene (thio) barbituric acids and pyrano [2,3-d] pyrimidinone (thiones) derivatives. For the
130
optimization of the reaction conditions, the effect of different factors including the catalyst loading, temperature, and solvent in the
131
preparation of 4-chlorobenzaldehyde derivatives of both of the requested target molecules was studied.
132
3.2.1. Optimization step for the preparation of 5-arylidene (thio)barbituric acid derivatives in the presence of [H2-pip][H2PO4]2
133
Preforming the reaction in the absence of the catalyst and solvent did not led to noticeable product. Also, the reaction in the absence
134
of solvent even with catalyst couldn’t provide the product. In the same way, no significant product was observed when the mixture
135
of the reaction was refluxed in chloroform. Refluxing of the mixture of the reaction in acetonitrole resulted in some product, but the
136
reaction was not completed, as like as heating in pure water at 50°C. The reaction led to the product in refluxing water, ethanol or a
137
mixture of them, but the best results were obtained when the reaction is perfoemed in the mixture of water/ethanol (1:1) at 80°C.
138
Also, the optimum amounts of the catalyst is determind as 5 mol% (Tables 1 and 2).
139
After optimization and determination of the best conditions for both reactions, various types of aldehydes containing electron-
140
donating or electron-withdrawing groups and heterocylic aldehydes were subjected to the mentioned reactions. All of them reacted
141
well in the reaction to give their corresponding products in high yields during short reaction times. No significant difference for the
142
substituent effect was observed in comparison but in the case of thiobarbituric acid derivatives, the rates and yields of the reactions
143
were ralatively lower than the reaction of barbituric acid derivatives (Tables 3 and 4).
144
3.2.2. Reusability of the catalyst
145
In order to show the reusability potential of the catalyst, the synthesis of compounds 1e and 2e was studied again. In these studies
146
and after the completion of the reaction, the product was isolated by filtration and the same reaction repeated in the filtrated solution
147
without addition of extra amounts of the catalyst. The results show that this catalyst can be reused for four times in both of the
148
mentioned reactions without significant loss of its catalytic activity (Figures 6 and 7).
149
3.2.3. Comparison of the catalitic ability
150
In order to show the catalytic ability of [H2-pip][H2PO4]2, the resuls related to preparation of compounds 1e and 2e are compared
151
with the same results obtained using other catalysts. In all cases, the introduced catalyst had one or more advantages from the
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153
made the catalyst relatively green in comparison to some other ones (Tables 5 and 6).
154
3.3. Mechanistic study
155
The proposed mechanism for the mentioned reactions is shown in Scheme 3. On the basis of this scheme, the catalyst enolized
156
(thio)barbituric acid attacks to the aldehyde which is also activated by the acidic proton of the catalyst. After elimination of water
157
molecule, 5-arylidene (thio)barbituric acid derivative is achieved.
158
In the case of pyrano[2,3-d]pyrimidinone (thione) products, the produced 5-arylidene (thio)barbituric acid is attacked by a molecule
159
of malononitrile which is activated by the catalyst. After a keto-enol tautomerization, cyclization occurs by nucleophilic attack of
160
the hydroxyl group to the activated nitrile group. At the end, with imine-enamin tautomerization, the expected products can be
161
obtained (Scheme 3).
162
4. Conclusion
163
In this study, we prepared a new acidic ionic salt by simple addition of phosphoric acid to piperazine and investigate its catalytic
164
activity in the synthesis of 5‐arylidenepyrimidine‐2,4,6(1H,3H,5H)‐trione and pyrano[2,3‐d]pyrimidinone derivatives. The
165
introduced catalyst has the advantages of similar Bronested ionic liquids, including the ability of being recover, high thermal
166
stability and non-hygroscopic nature which causes it to be stocked to store and use for a long time. Also, it is very suitable to be
167
used in humid climates.
168
Acknowledgments
169
We are thankful to the Research Council of the University of Guilan for the partial support of this research.
170
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Scheme. 1. Preparation of piperazine-1,4-diium dihydrogen phosphate.
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Fig. 1 The FT-IR spectra of piperazine (a) and piperazine-1,4-diium dihydrogen phosphate (b).
10
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Fig. 2 The 1H NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
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Fig. 3 The 13C NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
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Fig. 4 The 31P NMR spectrum of piperazine-1,4-diium dihydrogen phosphate.
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Fig. 5 The mass spectrum of piperazine-1,4-diium dihydrogen phosphate.
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Scheme 2. Synthesis of 5-arylidene barbituric acid and pyrano[2,3d]pyrimidinone derivatives using [H2-pip][H2PO4]2 under optimized conditions.
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ACCEPTED MANUSCRIPT Table 1. Optimization of the reaction conditions for the preparation of 5-arylidene barbituric acid derivative of 4-chlorobenzaldehyde. Entry
Catalyst (mol%)
Solvent
Temperature (°C)
Time (min.)
Yield (%) (isolated)
1
-
-
80-100
100
trace*
2
5
-
80-100
100
trace*
3
5
CHCl3
Reflux
100
trace*
5
CH3CN
Reflux
100
60
5
H₂O
50
65
68
6
5
H₂O
80
40
7
5
H2O
Reflux
35
8
5
EtOH
Reflux
50
9
3.5
H₂O/EtOH (1:1)
80
35
10
5
H₂O/EtOH (1:1)
80
20
11
6.4
H₂O/EtOH (1:1)
80
12
5
H₂O/EtOH (2:1)
80
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4 5
81
84
72
83 96
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20
86
38
88
* Reaction was not completed.
280 281 282
Table 2. Optimization of the reaction conditions for the preparation of pyrano[2,3-d] pyrimidinone derivative of 4-chlorobenzaldehyde. Catalyst (mol%)
Solvent
1
-
-
2
5
-
3
5
CHCl3
4
5
5
5
6
5
7
5
8
5
283 284
Yield (%) (isolated)
80-100
120
Trace*
80-100
120
Trace*
Reflux
120
Trace*
CH3CN
Reflux
120
Mixture
EtOH
Reflux
45
72
H₂O
50
65
68
H₂O
80
40
81
H2O
Reflux
30
84
3.5
H₂O/EtOH (1:1)
50
35
83
5
H₂O/EtOH (1:1)
80
24
95
AC C
10
Time (min)
EP
9
Temperature (°C)
TE D
Entry
M AN U
279
11
6.4
H₂O/EtOH (1:1)
Reflux
20
92
12
5
H₂O/EtOH (2:1)
80
40
87
* Reaction was not completed.
16
EP
TE D
Scheme 3. The plausible mechanisms of the studied reactions in the presence of [H2-pip][H2PO4]2.
AC C
285 286 287
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
17
ACCEPTED MANUSCRIPT 96
24
22
89
26 Yield(%) Time(min)
Time(min)
1 20
2 22
3 24
4 26
Yield(%)
96
94
91
89
SC
Fig. 6 Reusability of the catalysts in the preparation of 5-arylidene barbituric acid derivative of 4-chlorobenzaldehyde.
95 100 80 60 40
24
93
90
29
26
TE D
20
M AN U
288 289 290 291 292 293 294
20
91
RI PT
100 80 60 40 20 0
94
87
32
Yield (%) Time (min)
0
298
3 29
4 32
Yield (%)
95
93
90
87
EP
296 297
2 26
Fig. 7 Reusability of the catalysts in the preparation of pyrano[2,3-d]pyrimidinone derivative of 4- chlorobenzaldehyde .
AC C
295
Time (min)
1 24
18
ACCEPTED MANUSCRIPT Table 3. Synthesis of different derivatives of 5-arylidene barbituric acids. X
Symbol
Time (min.)
Yield (%)
1
C6H5CHO
O
1a
35
74
249-251
249-252 [68]
2
4-FC6H4CHO
O
1b
30
87
>300
>300 [68]
3
2-ClC6H4CHO
O
1c
25
92
250-252
249-251 [68]
4
3-ClC6H4CHO
O
1d
30
90
274–276
275–277 [68]
5
4-ClC6H4CHO
O
1e
20
96
>300
298-300 [68]
6
4-BrC6H4CHO
O
1f
30
95
292-294
292-294 [68]
7
2-NO₂C6H4CHO
O
1g
20
91
272-274
271-273 [68]
8
3-NO₂C6H4CHO
O
1h
28
90
226–228
226–228 [68]
9
4-NO₂C6H4CHO
O
1i
22
93
270–272
268–270 [66]
10
4-OHC6H4CHO
O
1j
20
90
>300
>300 [68]
11
2-OCH₃C6H4CHO
O
12
3-OCH₃C6H4CHO
O
13
4-OCH₃C6H4CHO
O
14
4-CH₃C6H4CHO
O
15
Terephthalaldehyde
O
16
Cinnamaldehyde
O
17
Furfural
18 19
21
SC
M AN U 14
85
270-272
270-271 [68]
1l
45
88
225-227
227-230[35]
1m
35
89
295-297
294-297 [68]
1n
30
94
278-280
277-280 [68]
1o
15
90
>300
>300 [68]
1p
20
89
267-269
267-268 [68]
O
1q
15
87
258-260
258-260 [66]
4-FC6H4CHO
S
1r
30
91
214-216
218-219 [71]
4-ClC6H4CHO
S
1s
25
90
287–290
287–290 [69]
2-NO₂C6H4CHO
S
1t
30
87
248-250
246-250 [69]
3-NO₂C6H4CHO
S
1u
35
85
266-268
266-268 [69]
TE D
1k
AC C
a
RI PT
Aldehyde
20
300 301 302
m.p. (°C) Reported Observed [ref.]
Entry
EP
299
Isolated yields.
19
ACCEPTED MANUSCRIPT Table 4. Synthesis of different derivatives of pyrano[2,3,d] pyrimidinone(thione) derivatives. Entry
Symbol
Time (min.)
Yield (%)
m.p. (°C) Observed
Reported [ref.]
O
2a
13
79
205-207
206-209 [72]
2
4-FC6H4CHO
O
2b
20
93
258-260
256-260 [69]
3
2-ClC6H4CHO
O
2c
20
92
214-216
212-215 [72]
4
3-ClC6H4CHO
O
2d
25
93
242-243
241-243 [68]
5
4-ClC6H4CHO
O
2e
24
95
238-240
237-240 [69]
6
4-BrC6H4CHO
O
2f
35
95
229-231
229-231 [69]
7
2-NO₂C6H4CHO
O
2g
24
86
255-258
256-258 [66]
8
3-NO₂C6H4CHO
O
2h
25
90
268-270
269-270 [66]
9
4-NO₂C6H4CHO
O
2i
30
89
237-238
237-239 [66]
10
4-OHC6H4CHO
O
11
2-OCH₃C6H4CHO
O
12
3-OCH₃C6H4CHO
O
13
4-OCH₃C6H4CHO
O
14
4-CH₃C6H4CHO
O
15
Terephthalaldehyde
16
M AN U
SC
RI PT
C6H5CHO
30
70
>300
>300 [66]
2k
30
81
220-222
221-222 [29]
2l
30
86
236-237
236-237 [66]
2m
30
90
281-282
280-284[68]
2n
45
88
225-227
223-225 [68]
O
2o
25
93
>300
>300 [68]
Furfural
O
2p
45
82
280-281
281-282 [57]
17
4-ClC6H4CHO
S
2q
40
91
>300
>300 [69]
18
3-NO₂C6H4CHO
S
2r
50
85
234-236
234-235[69]
S
2s
40
78
233-235
234-235[69]
TE D
2j
4-NO₂C6H4CHO
Isolated yields.
AC C
a
X
1
19
304
Aldehyde
EP
303
20
ACCEPTED MANUSCRIPT
Catalyst
Amount of catalyst
Conditions
Time (min.)
Yield (%)
Ref.
1
BF3/nano-γ-Al2O3
60 mg
Ethanol, R.T.
30
84
[35]
2
NH2SO3H
100 mol%
Grinding-laying
180
93
[39]
3
PVP-Ni Nps
100 mg
Ethylene glycol, 50 °C
10-15
93
[40]
4
[bmim]BF4
0.2 mL
Grinding-laying
5
EAN
2 mL
R.T.
6
CTMAB
50 mol%
H2O, R.T.
7
CH3COONa
100 mol%
Grinding
8
CMZO
200 mg
EtOH, 60-70 °C
9
p-Dodecylbenzene sulfonic acid (DBSA)
30 mol%
H2O, reflux
10
[H2-pip][H2PO4]2
5 mol%
RI PT
Entry
78
[41]
180
83
[42]
30
82
[43]
10
91
[44]
60
85
[45]
67
62
[73]
20
96
This work
M AN U
SC
120
H2O/EtOH (1:1) 80°C
Table 6. Comparison of catalytic activity of [H2-pip][H2PO4]2 with some reported catalysts in the
synthesis of 4-chlorophenyl derivative of pyrano[2,3,d] pyrimidinone. Amount of catalyst
Conditions
Time (min.)
Yield (%)
Ref.
1
Al-HMS-20
30 mg
EtOH, R.T.
720
92
[57]
2
[BMIm]BF4
30 mg
90 °C, S.F.
180
92
[41]
3
CaHPO4
10 mol%
H2O/EtOH (4:1)
120
92
[58]
4
Choline chloride.ZnCl2
50 mol%
EtOH, 75 °C
120
94
[59]
5
Boric acid
10 mol%
110
85
[61]
6
Nano-titania sulfuric acid
20 mg
60
89
[61]
TE D
Entry
Catalyst
AC C
307 308 309 310
Table 5. Comparison of catalytic activity of [H2-pip][H2PO4]2 with some reported catalysts in the synthesis of 4-chlorophenyl derivative of 5-arylidene barbituric acid.
EP
305 306
THF/H2O (4:1), Reflux EtOH/H2O (19:1), Reflux
7
Zn[L-proline]2
17 mol%
EtOH, Reflux
50
90
[60]
8
ZnO@CuO
30 mg
H2O, Reflux
12
91
[62]
9
SBA-Pr-SO3H
20 mg
S.F., 140 °C
45
30
[56]
10
nano Al2O3
20 mol%
H2O: EtOH,reflux
4h
87
[74]
11
Trichloroisocyanur ic acid
10 mol%
H2O, Reflux
90
93
[75]
12
[H2-pip][H2PO4]2
5 mol%
H2O/EtOH (1:1) 80°C
24
95
This work
311
21
AC C
EP
TE D
M AN U
SC
RI PT
ACCEPTED MANUSCRIPT
ACCEPTED MANUSCRIPT
Highlights Synthesis, characterization and utilization of an ionic salt base on piperazine.
•
Use of environmentally friendly and nontoxic phosphoric acid for the catalyst.
•
Various spectroscopic characterization including FT-IR, 1H NMR, 13C NMR and 31P
RI PT
•
NMR.
High product yields and rates of the reaction and good reusability of the catalyst.
•
Preforming the reaction in green media.
AC C
EP
TE D
M AN U
SC
•