Next Article in Journal
N4-(2-Amino-4-fluorophenyl)-N1-(3-{2-[2-(3-{[2-(2,6-dioxo-3-piperidyl)-1,3-dioxoisoindolin-4-yl]amino}propoxy)ethoxy]ethoxy}propyl)terephthalamide
Previous Article in Journal
19β,28-Epoxy-18α-olean-3β-ol-2-furoate from Allobetulin (19β,28-Epoxy-18α-olean-3β-ol)
 
 
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Short Note

N2,N6-Bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide

1
Faculty of Food Technology Osijek, Josip Juraj Strossmayer University of Osijek, Franje Kuhača 18, 31000 Osijek, Croatia
2
Faculty of Chemistry and Technology, University of Split, R. Boškovića 35, 21000 Split, Croatia
*
Author to whom correspondence should be addressed.
Molbank 2022, 2022(4), M1500; https://doi.org/10.3390/M1500
Received: 20 October 2022 / Revised: 14 November 2022 / Accepted: 16 November 2022 / Published: 21 November 2022

Abstract

:
A green chemistry method was applied in the synthesis of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide. The desired compound was synthesized mechanochemically, using a choline chloride-based deep eutectic solvent as a catalyst. The synthesis took 20 min and the new compound was characterized using different spectral methods.

1. Introduction

Quinazolinones, a group of nitrogen containing heterocyclic compounds, are very prominent medicinal and pharmaceutical scaffolds, showing a wide range of biological activities. Their activities include antibacterial [1,2,3,4], antifungal, antitumor [5,6,7,8], antidiabetic [9,10,11], anti-inflammatory [12,13,14] and many others. Many researchers these days are investigating their synthesis, finding the most efficient synthetic paths and synthesizing different derivatives and hybrids. Our investigation was based on the synthesis of quinazolinone–pyridine hybrids, since pyridine derivatives have also proven to be biologically active [15,16]. Keeping the green chemistry principles in mind [17], we applied a mechanochemical procedure in the synthesis of such hybrids. Since conventional synthetic methods usually have adverse effects on the environment due to the utilization of high volumes of volatile organic solvents [18], high energy consumption and waste production, green synthetic methods are becoming more prominent in recent times [19]. Mechanochemistry, as one of these methods, has found applications in many chemical processes. Mechanochemical reactions can be performed solvent-free and at low temperatures due to the combination of mechanical and chemical phenomena. Reaction times are usually reduced, while the post-synthetic procedures are minimal, with the overall process being faster and cleaner [20].

2. Results and Discussion

A new compound N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide was synthesized from 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (1) and pyridine-2,6-dicarbohydrazide (2). First, 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (1) was synthesized in a microwave-assisted reaction according to Figure 1, as described in our previous work [21].
Then, pyridine-2,6-dicarbohydrazide (2) was synthesized (Figure 2) according to Molnar et al. [22].
Afterwards, the synthesis of the desired compound was performed mechanochemically, using freshly prepared 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (1) and pyridine-2,6-dicarbohydrazide (2) and1 mL of choline chloride:urea (1:2) deep eutectic solvent (DES) (Figure 3). The mixture was ball-milled for 20 min and upon completion of the reaction, water was added to the mixture. The new compound was recrystallized from methanol and obtained with 57% yield. The melting point, NMR and mass spectra were recorded.
The 1H NMR spectra reveal some characteristic peaks. Quinazolinone C-2 methyl protons show singlet peaks at 2.51 ppm, aromatic protons peaks are found at 7.52–8.47 ppm, while –NH- protons are found at 12.24 and 12.15 ppm. The 13C NMR spectra also show peaks characteristic of a –CH3 carbon at 21.8 ppm and characteristic aromatic carbon peaks (full spectra available in Supplementary Materials).
This synthetic pathway has green character due to utilization of DES as a catalyst, which is biodegradable and non-toxic, while ball-milling proves to be time and energy efficient, yielding the final compound in high purity. The synthesis of similar compounds, using benzoxazinone and different amines, is usually performed conventionally, but in most cases requires longer times, higher temperatures or extensive purification [23,24,25,26].

3. Materials and Methods

All chemicals were purchased from commercial suppliers and were used as such. Choline chloride (99%) was purchased from Acros Organics (Geel, Belgium) and urea (p.a.) was purchased from Gram Mol. Aluminum plates coated with silica gel fluorescent indicator F254 (Kieselgel 60) were used for thin-layer chromatography, while benzene: acetone: acetic acid (8:1:1) was used as a mobile phase. TLC plates were monitored using HP-UVIS cabinet (Biostep GmbH, Burkhardtsdorf, Germany). The Electrothermal IA9100 melting point apparatus (Electrothermal Engineering Ltd., Rochford, UK) was used for melting point determination. NMR spectra were recorded on a Bruker 600 MHz spectrometer (Bruker Biospin, Rheinstetten, Germany). Mass spectra were recorded on an LC/MS/MS API 2000 (Foster City, CA, USA). IR spectra were recorded on an Agilent Cary 630 FTIR Spectrometer (Agilent Technologies, Santa Clara, CA, USA). The synthesis was performed using an Omni Bead Ruptor 12 Homogenizer (OMNI International, Kennesaw, GA, USA).
Synthesis of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide.
To a reaction mixture of 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one (1 mmol, 287.05 mg) and pyridine-2,6-dicarbohydrazide (0.5 mmol, 97.6 mg), 1 mL of ChCl: urea DES and 3 g of ceramic beads was added. The mixture was subjected to ball-milling for 20 min at 6 m/s. The reaction was monitored by TLC (benzene:acetone:acetic acid 8:1:1) and quenched with water. Upon precipitation, the product was filtered off and recrystallized from methanol with 57% yield.
Mp = 249–251 °C; Rf = 0.58; MS (ESI): m/z = 732.10 [M-H] (Mr = 733.26). 1H NMR (600 MHz, DMSO-d6): δ/ppm 12.24 (1H, s, -NH-); 12.15 (1H, s, -NH-); 8.47–8.38 (5H, m, arom.); 8.22–8.18 (2H, m, arom.); 7.52 (2H, dd, J = 8.6; 1.2 Hz, arom.); 2.51 (6H, s, -CH3). 13C NMR (150 MHz, DMSO-d6): δ/ppm 162.9; 162.8; 158.3; 158.1; 157.3; 147.1; 146.3; 144.2; 141.2; 135.1; 129.8; 127.1; 122.6; 92.7; 21.8.

4. Conclusions

A new derivative of dipicolinic acid was mechanochemically synthesized. The synthesis was performed using benzoxazinone, pyridine-2,6-dicarbohydrazide and choline chloride: urea DES as a catalyst, and was performed in 10 min. Our method for this synthesis is green, efficient and short.

Supplementary Materials

The following supporting information can be downloaded online, Figure S1: 1H NMR spectra of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide; Figure S2: Mass spectra of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide; Figure S3: 13C NMR spectra of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide; Figure S4: IR spectra of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide; Molfile of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide.

Author Contributions

Conceptualization, M.M.; methodology, M.K.; software, M.M. and M.K.; validation, M.M., M.K. and I.J.; formal analysis, M.M.; investigation, M.K.; resources, M.M.; data curation, I.J.; writing—original draft preparation, M.M.; writing—review and editing, M.M. and I.J.; visualization, M.K.; supervision, M.M.; project administration, M.M.; funding acquisition, M.M. All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by Croatian Science Foundation under the project “Green Technologies in Synthesis of Heterocyclic compounds” (UIP-2017-05-6593).

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Acknowledgments

We would like to thank the Croatian Science Foundation for funding the project “Green Technologies in Synthesis of Heterocyclic compounds” (UIP-2017-05-6593).

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Sayyed, M.A.; Mokle, S.S.; Vibhute, Y.B. Synthesis of 6-Iodo/Bromo-3-Amino-2-Methylquinazolin-4(3H)-Ones by Direct Halogenation and Their Schiff Base Derivatives. ARKIVOC 2006, 2006, 221–226. [Google Scholar] [CrossRef]
  2. Atia, A.J.K.; Al-Mufrgeiy, S.S. Synthesis and Antibacterial Activities of New 3-Amino-2-Methyl-Quinazolin-4 (3H)-One Derivatives. Am. J. Chem. 2012, 2, 150–156. [Google Scholar] [CrossRef]
  3. Gatadi, S.; Gour, J.; Shukla, M.; Kaul, G.; Das, S.; Dasgupta, A.; Malasala, S.; Borra, R.S.; Madhavi, Y.V.; Chopra, S.; et al. Synthesis of 1,2,3-Triazole Linked 4(3H)-Quinazolinones as Potent Antibacterial Agents against Multidrug-Resistant Staphylococcus Aureus. Eur. J. Med. Chem. 2018, 157, 1056–1067. [Google Scholar] [CrossRef]
  4. Masri, A.; Anwar, A.; Khan, N.A.; Shahbaz, M.S.; Khan, K.M.; Shahabuddin, S.; Siddiqui, R. Antibacterial Effects of Quinazolin-4(3H)-One Functionalized-Conjugated Silver Nanoparticles. Antibiotics 2019, 8, 179. [Google Scholar] [CrossRef] [PubMed]
  5. Long, S.; Resende, D.I.S.P.; Kijjoa, A.; Silva, A.M.S.; Pina, A.; Fernández-Marcelo, T.; Vasconcelos, M.H.; Sousa, E.; Pinto, M.M.M. Antitumor Activity of Quinazolinone Alkaloids Inspired by Marine Natural Products. Mar. Drugs 2018, 16, 261. [Google Scholar] [CrossRef] [PubMed]
  6. Lai, K.-C.; Chia, Y.-T.; Yih, L.-H.; Lu, Y.-L.; Chang, S.-T.; Hong, Z.-X.; Chen, T.-L.; Hour, M.-J. Antitumor Effects of the Novel Quinazolinone Holu-12: Induction of Mitotic Arrest and Apoptosis in Human Oral Squamous Cell Carcinoma CAL27 Cells. Anticancer Res. 2021, 41, 259–268. [Google Scholar] [CrossRef]
  7. Wdowiak, P.; Matysiak, J.; Kuszta, P.; Czarnek, K.; Niezabitowska, E.; Baj, T. Quinazoline Derivatives as Potential Therapeutic Agents in Urinary Bladder Cancer Therapy. Front. Chem. 2021, 9, 765552. [Google Scholar] [CrossRef]
  8. Niu, Z.; Ma, S.; Zhang, L.; Liu, Q.; Zhang, S. Discovery of Novel Quinazoline Derivatives as Potent Antitumor Agents. Molecules 2022, 27, 3906. [Google Scholar] [CrossRef]
  9. Saeedi, M.; Mohammadi-Khanaposhtani, M.; Pourrabia, P.; Razzaghi, N.; Ghadimi, R.; Imanparast, S.; Faramarzi, M.A.; Bandarian, F.; Esfahani, E.N.; Safavi, M.; et al. Design and Synthesis of Novel Quinazolinone-1,2,3-Triazole Hybrids as New Anti-Diabetic Agents: In Vitro α-Glucosidase Inhibition, Kinetic, and Docking Study. Bioorg. Chem. 2019, 83, 161–169. [Google Scholar] [CrossRef]
  10. Khalifa, M.M.; Sakr, H.M.; Ibrahim, A.; Mansour, A.M.; Ayyad, R.R. Design and Synthesis of New Benzylidene-Quinazolinone Hybrids as Potential Anti-Diabetic Agents: In Vitro α-Glucosidase Inhibition, and Docking Studies. J. Mol. Struct. 2022, 1250, 131768. [Google Scholar] [CrossRef]
  11. Barmak, A.; Niknam, K.; Mohebbi, G. Synthesis, Structural Studies, and α-Glucosidase Inhibitory, Antidiabetic, and Antioxidant Activities of 2,3-Dihydroquinazolin-4(1H)-Ones Derived from Pyrazol-4-Carbaldehyde and Anilines. ACS Omega 2019, 4, 18087–18099. [Google Scholar] [CrossRef] [PubMed]
  12. Chaitanya, P.; Reddy, G.D.; Varun, G.; Srikanth, L.M.; Prasad, V.V.S.R.; Ravindernath, A. Design and Synthesis of Quinazolinone Derivatives as Anti-Inflammatory Agents: Pharmacophore Modeling and 3D QSAR Studies. Med. Chem. 2014, 10, 711–723. [Google Scholar] [CrossRef] [PubMed]
  13. Krishnarth, N.; Verma, S.K.; Chaudhary, A. Synthesis and Anti-Inflammatory Activity of Some Novel Quinazolinone Derivatives. FABAD J. Pharm. Sci. 2020, 45, 205–210. [Google Scholar]
  14. Poojari, S.; Krishnamurthy, G.; KS, J.K.; Kumar, S.; Naik, S. Anti-Inflammatory, Antibacterial and Molecular Docking Studies of Novel Spiro-Piperidine Quinazolinone Derivatives. J. Taibah Univ. Sci. 2017, 11, 497–511. [Google Scholar] [CrossRef]
  15. Altaf, A.A.; Shahzad, A.; Gul, Z.; Rasool, N.; Badshah, A.; Lal, B.; Khan, E. A Review on the Medicinal Importance of Pyridine Derivatives. J. Drug Des. Med. Chem. 2015, 1, 1. [Google Scholar] [CrossRef]
  16. Ling, Y.; Hao, Z.-Y.; Liang, D.; Zhang, C.-L.; Liu, Y.-F.; Wang, Y. The Expanding Role of Pyridine and Dihydropyridine Scaffolds in Drug Design. Drug Des. Dev. Ther. 2021, 15, 4289–4338. [Google Scholar] [CrossRef]
  17. Anastas, P.T.; Warner, J.C. Green Chemistry: Theory and Practice; Oxford University Press: Oxford, UK, 2000; ISBN 978-0-19-850698-0. [Google Scholar]
  18. David, E.; Niculescu, V.-C. Volatile Organic Compounds (VOCs) as Environmental Pollutants: Occurrence and Mitigation Using Nanomaterials. Int. J. Environ. Res. Public Health 2021, 18, 13147. [Google Scholar] [CrossRef]
  19. Bedlovičová, Z. Green Synthesis—An Overview. In Green Synthesis of Silver Nanomaterials; Elsevier Inc.: Amsterdam, The Netherlands, 2022; pp. 547–569. [Google Scholar]
  20. Do, J.-L.; Friščić, T. Mechanochemistry: A Force of Synthesis. ACS Cent. Sci. 2017, 3, 13–19. [Google Scholar] [CrossRef]
  21. Komar, M.; Prašnikar, F.; Kraljević, T.G.; Aladić, K.; Molnar, M. 3-Amino-2-Methylquinazolin-4-(3H)-One Schiff Bases Synthesis—A Green Chemistry Approach—A Comparison of Microwave and Ultrasound Promoted Synthesis with Mechanosynthesis. Curr. Green Chem. 2021, 8, 62–69. [Google Scholar] [CrossRef]
  22. Molnar, M.; Pavić, V.; Šarkanj, B.; Čačić, M.; Vuković, D.; Klenkar, J. Mono- and Bis-Dipicolinic Acid Heterocyclic Derivatives—Thiosemicarbazides, Triazoles, Oxadiazoles and Thiazolidinones as Antifungal and Antioxidant Agents. Heterocycl Commun 2017, 23, 35–42. [Google Scholar] [CrossRef]
  23. Ramanathan, M.; Hsu, M.-T.; Liu, S.-T. Preparation of 4(3H)-Quinazolinones from Aryldiazonium Salt, Nitriles and 2-Aminobenzoate via a Cascade Annulation. Tetrahedron 2019, 75, 791–796. [Google Scholar] [CrossRef]
  24. Rajput, C.S.; Kumar, A.; Kumar Bhati, S.; Singh, J. Synthesis and Antiinflammatory Activity of 2-[5′-(4-Pyridinyl)-1′,2′,3′-Oxadiazol-2-Yl-Thiomethyl]-3-Substituted-Aryl-6-Substituted-Quinazolin-4-Ones. Asian J. Chem. 2008, 20, 6246–6252. [Google Scholar]
  25. Marinho, E.; Proença, M.F. The Reaction of 2-(Acylamino)Benzonitriles with Primary Aromatic Amines: A Convenient Synthesis of 2-Substituted 4-(Arylamino)Quinazolines. Synthesis 2015, 47, 1623–1632. [Google Scholar] [CrossRef]
  26. Ajani, O.O.; Audu, O.Y.; Germann, M.W.; Bello, B.L. Expeditious Synthesis and Spectroscopic Characterization of 2-Methyl-3-Substituted-Quinazolin-4(3H)-One Derivatives. Orient. J. Chem. 2017, 33, 562–574. [Google Scholar] [CrossRef]
Figure 1. Microwave-assisted synthesis of 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one.
Figure 1. Microwave-assisted synthesis of 6-iodo-2-methyl-4H-benzo[d][1,3]oxazin-4-one.
Molbank 2022 m1500 g001
Figure 2. Synthesis of pyridine-2,6-dicarbohydrazide.
Figure 2. Synthesis of pyridine-2,6-dicarbohydrazide.
Molbank 2022 m1500 g002
Figure 3. Synthesis of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide.
Figure 3. Synthesis of N2,N6-bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide.
Molbank 2022 m1500 g003
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Share and Cite

MDPI and ACS Style

Molnar, M.; Komar, M.; Jerković, I. N2,N6-Bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide. Molbank 2022, 2022, M1500. https://doi.org/10.3390/M1500

AMA Style

Molnar M, Komar M, Jerković I. N2,N6-Bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide. Molbank. 2022; 2022(4):M1500. https://doi.org/10.3390/M1500

Chicago/Turabian Style

Molnar, Maja, Mario Komar, and Igor Jerković. 2022. "N2,N6-Bis(6-iodo-2-methyl-4-oxoquinazolin-3(4H)-yl)pyridine-2,6-dicarboxamide" Molbank 2022, no. 4: M1500. https://doi.org/10.3390/M1500

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop