1,3-Bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)imidazolidine-4,5-dione

Abstract

A thieno[2,3-d]pyrimidine derivative 3 bearing a 4,5-imidazolidinedione moiety, 1,3-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)imidazolidine-4,5-dione, was efficiently synthesized in 66% yield by the reaction of N,N′-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine 2 with oxalyl chloride in the presence of pyridine in refluxing dichloroethane for 10 h. The structure of the new synthesized compounds was fully characterized by 1H, 13C NMR, IR spectroscopy, mass-spectrometry and elemental analysis.

1. Introduction

Thienopyrimidine compounds continue to attract considerable interest in medicinal chemistry because of their structural relationship with the purine base and therapeutic potential [1,2]. Among them, thieno[2,3-d]pyrimidine derivatives are known to have remarkable biological properties, such as anticancer [3], antibacterial [4], anti-inflammatory [5,6], antiviral [7], and antimalarial activities [8]. Imidazolidinedione derivatives, including hydantoin (2,4-imidazolidinedione) as a useful scaffold, displayed diverse biological and pharmacological activities, such as antimicrobial [9], anticonvulsant [10], antitumor [11] and antiviral activities [12]. Recently, 2,5-imidazolidinedione derivatives were prepared as histone deacetylase 6 (HDAC6) selective inhibitors for various human diseases, including diverse neurodegenerative diseases and cancer [13]. However, there are very few reports on the synthesis of 4,5-imidazolidinedione compounds [14,15,16]. We report herein the synthesis of a hybrid compound 3, thieno[2,3-d]pyrimidine derivative bearing a 4,5-imidazolidinedione moiety.

2. Results

The synthetic route to the new compound 3 is described in Scheme 1. When thieno- [2,3-d]pyrimidin-4-amine 1 [17] was allowed to react with aqueous formaldehyde in 1,4-dioxane at 100 °C using a modified method [18], a new compound 2, N,N′-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine, was formed in 75% yield. Subsequent cyclization of 2 with oxalyl chloride in the presence of pyridine in refluxing dichloroethane gave a new cyclic compound 3 in 66% yield.

The ¹H NMR spectrum of 2 showed a sharp triplet at δ 5.29 ppm due to methylene protons between two NHs, and a triplet at δ 7.34 ppm for NH protons (J = 4.7 Hz) (Supplementary Materials). It presented a sharp signal at δ 8.38 ppm attributed to a pyrimidine proton in the thieno[2,3-d]pyrimidine ring, and showed three multiplets at δ 2.89, 2.74 and 1.80 ppm for cyclohexyl protons. In the ¹³C NMR spectrum, compound 2 showed a peak at δ 47.5 ppm for the methylene carbon between two NHs, including six peaks for the thienopyrimidine ring at δ 164.9, 156.2, 152.4, 132.3, 126.2 and 115.8 ppm. The IR spectrum revealed a characteristic NH absorption at 3446 cm⁻¹. The mass spectrum showed m/z = 423 (MH⁺) corresponding to the molecular formula, C₂₁H₂₂N₆S₂. The structure of 3 was also confirmed by ¹H, ¹³C NMR, IR spectroscopy, mass spectrometry and elemental analysis (Supplementary Materials). The ¹H NMR spectrum of 3 (NMR solvent: CD₃OD + CD₂Cl₂) exhibited the expected pattern with a sharp singlet at δ 5.38 ppm slightly upfield for the methylene group of a cyclic 4,5-imidazolidinedione moiety. One single peak at δ 8.94 attributed to a pyrimidine proton in the thieno[2,3-d]pyrimidine ring, and three multiplets at δ 2.99, 2.88 and 1.95 ppm were shown due to cyclohexyl protons. In the ¹³C NMR spectrum, compound 3 showed a peak δ 157.8 ppm for the newly formed amide carbon, including six peaks for thienopyrimidine at δ 171.9, 152.2, 148.3, 141.9, 127.8 and 127.3 ppm. The methylene carbon of a cyclic 4,5-imidazolidinedione moiety was shown at 61.1 ppm at a downfield when compared to the methylene carbon of 2. The IR spectrum revealed a characteristic carbonyl absorption at 1752 cm⁻¹ and missing NH absorption. The mass spectrum showed m/z = 476 (M⁺) corresponding to the molecular formula, C₂₃H₂₀N₆O₂S₂. Elemental analysis also provided satisfactory results. The compound 3 showed low solubility in most common solvents, and a high melting point (mp = 298–299 °C), suggesting high thermal stability.

In conclusion, a hybrid compound 3, thieno[2,3-d]pyrimidine derivative 3 bearing a 4,5-imidazolidinedione moiety was synthesized efficiently by the reaction of N,N′-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine 2 with oxalyl chloride in the presence of pyridine in refluxing dichloroethane. This thieno[2,3-d]pyrimidine derivative could be used as a useful component of biologically active molecules for drug development.

3. Materials and Methods

3.1. General Information

All chemicals and reagents were purchased from Sigma-Aldrich (St. Louis, MO, USA) and TCI (Tokyo, Japan). The solvents used were purified using standard techniques. Melting point was determined on Kofler apparatus and was uncorrected. Thin-layer chromatography (TLC) was used to monitor reactions and performed using aluminum sheets precoated with silica gel 60 (HF₂₅₄, Merck, Waltham, MA, USA), and visualized with UV radiation (Fisher Scientific, Waltham, MA, USA). The ¹H and ¹³C NMR spectra were recorded in deuterated DMSO or MeOH/CH₂Cl₂ with TMS as the standard on a Bruker Avancell FT-NMR. The IR spectrum was recorded on Bruker Invenio FT-IR. The mass spectrum was obtained with Agilent 6890 Mstation instrument.

3.2. Synthesis of N,N′-Bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine (2)

A solution of thieno[2,3-d]pyrimidin-4-amine 1 (206 mg, 1.0 mmol) and formaldehyde (1.64 g of 37% aqueous solution, 1.5 mmol, 1.5 equiv) in 1,4-dioxane (15 mL) was heated at 100 °C with stirring. After completion of the reaction (5 h, monitored by TLC), the mixture was cooled to room temperature. The white precipitate was filtered, washed with cold 1,4-dioxane and dried. The crude product was recrystallized from chloroform as light-yellow solid of 2 in 75% yield (316 mg). Mp 255–256 °C; TLC R_f = 0.53 (dichloromethane:MeOH = 15:1). ¹H NMR (850 MHz, DMSO-d₆) (ppm) δ 8.38 (s, 2H), 7.34 (t, J = 4.7 Hz, 2H), 5.29 (t, J = 4.7 Hz, 2H), 2.89–2.88 (m, 4H), 2.75–2.73 (m, 4H), 1.82–1.78 (m, 8H). ¹³C NMR (213 MHz, DMSO-d₆) (ppm) δ 164.9, 156.2, 152.4, 132.3, 126.2, 115.8, 47.5, 25.4, 24.8, 22.0, 21.8. IR (KBr) 3446 (NH), 1671, 1548, 1482 cm⁻¹. MS (FAB) m/z = 423 (MH⁺, 76%). Anal. calcd. for C₂₁H₂₂N₆S₂, %: C, 59.69; H, 5.25; N, 19.89. Found, %: C, 59.40; H, 5.01; N, 19.99.

3.3. Synthesis of 1,3-Bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)imidazolidine-4,5-dione (3)

Oxalyl chloride (127 mg, 1.0 mmol) was added dropwise with ice-cooling to a solution of N,N′-bis(5,6,7,8-tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidin-4-yl)methanediamine 2 (300 mg, 0.7 mmol) in an anhydrous dichloroethane (15 mL) containing pyridine (160 mg, 2.0 mmol) under nitrogen. The reaction mixture was stirred at 0 °C to room temperature for 0.5 h, and kept at reflux for additional time. After completion of the reaction (10 h, monitored by TLC), the mixture was cooled and evaporated to dryness. The residue was dissolved in ethyl acetate (15 mL), washed with water and dried. The crude product was purified by recrystallization from methanol to afford a pale-greenish solid of 3 in 66% yield (220 mg). Mp 298–299 °C; TLC R_f = 0.63 (dichloromethane:MeOH = 17:1). ¹H NMR (500 MHz, CD₃OD + CD₂Cl₂) (ppm) δ 8.94 (s, 2H), 5.38 (s, 2H), 3.00–2.97 (m, 4H), 2.88 (m, 4H), 2.00–1.90 (m, 8H). ¹³C NMR (125 MHz, CD₃OD + CD₂Cl₂) (ppm) δ 171.9, 157.8, 152.2, 148.3, 141.9, 127.8, 127.3, 61.1, 26.7, 25.1, 23.1, 22.9. IR (KBr) 1752 (C=O), 1564, 1439 cm⁻¹. MS (FAB) m/z = 476 (M⁺, 36%). Anal. calcd. for C₂₃H₂₀N₆O₂S₂, %: C, 59.97; H, 4.23; N, 17.63. Found, %: C, 59.85; H, 4.11; N, 17.81.

Author Contributions

Conceptualization, Y.-H.S.; methodology, X.Y. and Y.-H.S.; investigation, X.Y. and S.M.K.; writing—original draft preparation, Y.-H.S.; writing—review and editing, Y.-H.S. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Not applicable.

Acknowledgments

This work was supported by Mokwon University.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Scheme

Scheme 1. Synthesis of the target compound 3.

Supplementary Materials

The following supporting information can be downloaded online. Figures S1–S8: ¹H NMR, ¹³C NMR, Mass and IR spectra of compounds 2 and 3.

References

1. Lagardèrè, P.; Fersing, C.; Masurier, N.; Lisowski, V. Thienopyrimidine: A promising Scaffold to access anti-infective agents. Pharmaceuticals; 2022; 15, 35.

2. Ali, E.M.H.; Abdel-Maksoud, M.S.; Oh, C.-H. Thieno[2,3-d]pyrimidines are a promising scaffold in medicinal chemistry: Recent advances. Bioorg. Med. Chem.; 2019; 27, pp. 1159-1194. [DOI: https://dx.doi.org/10.1016/j.bmc.2019.02.044] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30826188]

3. Li, L.; Liu, J.; Yang, J.; Zaho, H.; Deng, B.; Ren, Y.; Mai, R.; Huang, J.; Chen, J. Discovery of thieno[2,3-d]pyrimidine-based KRAS G12D inhibitors as potential anticancer agents via combinatorial virtual screening. Eur. J. Med. Chem.; 2022; 233, 114243. [DOI: https://dx.doi.org/10.1016/j.ejmech.2022.114243] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/35276423]

4. Gill, R.K.; Singh, H.; Raj, T.; Sharma, A.; Singh, G.; Bariwal, J. 4-Substituted thieno[2,3-d]pyrimidines as potent antibacterial agents: Rational dssign, microwave-assisted synthesis, biological evaluation and molecular docking studies. Chem. Biol. Drug Des.; 2017; 90, pp. 1115-1121. [DOI: https://dx.doi.org/10.1111/cbdd.13028] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28544494]

5. Zhang, Y.; Luo, L.; Han, C.; Lv, H.; Chen, D.; Shen, G.; Wu, K.; Pan, S.; Ye, F. Design, synthesis, and biological activity tetrahydrobenzo[4,5]thieno[2,3-d]pyrimidine derivatives an anit-inflammatory agents. Molecules; 2017; 22, 1960. [DOI: https://dx.doi.org/10.3390/molecules22111960] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29137170]

6. Jang, H.-J.; Kim, S.M.; Rho, M.C.; Lee, S.W.; Song, Y.-H. Synthesis of thienopyrimidine derivatives as inhibitors of STAT3 activation induced by IL-6. J. Microbiol. Biotechnol.; 2019; 29, pp. 856-862. [DOI: https://dx.doi.org/10.4014/jmb.1811.11046]

7. Bassetto, M.; Leyssen, P.; Neyts, J.; Yerukhimovich, M.M.; Frick, D.N.; Brancale, A. Computer-aided identification, synthesis and evaluation of substituted thienopyrimidines as novel inhibitors of HCV replication. Eur. J. Med. Chem.; 2016; 123, pp. 31-47. [DOI: https://dx.doi.org/10.1016/j.ejmech.2016.07.035]

8. Barrows, R.D.; Hammill, J.T.; Tran, M.C.; Falade, M.O.; Rice, A.L.; Davis, C.W.; Emge, T.J.; Rablen, P.R.; Kiplin Guy, R.; Knapp, S. Evaluation of 1,1-cyclopropylidene as a thioether isostere in the 4-thio-thienopyrimidine (TTP) series of antimalarials. Bioorg. Med. Chem.; 2020; 28, 115758. [DOI: https://dx.doi.org/10.1016/j.bmc.2020.115758]

9. Ali, O.M.; El-Sayed, W.A.; Eid, S.A.; Abdelwahed, N.A.M.; Abdel-Rahman, A.A.-H. Antimicrobial activity of new synthesized [(oxadiazolyl)methyl]phenytoin derivatives. Acta Polon. Pharm.; 2012; 69, pp. 657-667.

10. Thenmozhiyal, J.C.; Wong, P.T.-H.; Chui, W.-K. Anticonvulsant activity of phenylmethylenehydantoins: A structure-activity relationship study. J. Med. Chem.; 2004; 47, pp. 1527-1535. [DOI: https://dx.doi.org/10.1021/jm030450c] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/14998338]

11. Struck, R.F.; Kirk, M.C.; Rice, L.S.; Suling, W.J. Isolation, synthesis and antitumor evaluation of spirohydantoin aziridine, a mutagenic metabolite of spirohydantoin mustard. J. Med. Chem.; 1986; 29, pp. 1319-1321. [DOI: https://dx.doi.org/10.1021/jm00157a039]

12. Kim, D.; Wang, L.; Caldwell, C.G.; Chen, P.; Finke, P.E.; Oates, B.; MacCoss, M.; Mills, S.G.; Malkowitz, L.; Gould, S.L. et al. Discovery of human CCR5 antagonists containing hydantoins for the treatment of HIV-1 infection. Bioorg. Med. Chem. Lett.; 2001; 11, pp. 3099-3102. [DOI: https://dx.doi.org/10.1016/S0960-894X(01)00654-0]

13. Liang, T.; Xue, J.; Yao, Z.; Ye, Y.; Yang, X.; Hou, X.; Fang, H. Design, synthesis and biological evaluation of 3,4-disubstituted imidazolidine-2,5-dione derivatives as HDAC6 selective inhibitors. Eur. J. Med. Chem.; 2021; 221, 113526. [DOI: https://dx.doi.org/10.1016/j.ejmech.2021.113526]

14. Verardo, G.; Giumanini, A.G.; Gorassini, F.; Tolazzi, M.; Strazzolini, P. Heterocycles from heterocycles. 1,3-Diaryl-4,5-imidazolinediones from 1,3,5-triarylhexahydro-1,3,5-triazines and oxalyl chloride. Tetrahedron; 1993; 46, pp. 10609-10628. [DOI: https://dx.doi.org/10.1016/S0040-4020(01)81552-0]

15. Verardo, G.; Giumanini, A.G.; Gorassini, F.; Strazzolini, P. Heterocycles from heterocycles. 1,3-Dialkyl-4,5-imidazolinediones from 1,3,5-trialkylhexahydro-1,3,5-triazines and oxalyl chloride. Monatsh. Chem.; 1995; 126, pp. 103-105. [DOI: https://dx.doi.org/10.1007/BF00811763]

16. Ghandi, M.; Salimi, F. Synthesis of new 1,3-bis(heteroaryl)-4,5-imidazolinediones through reaction of N,N-bis(heteroaryl)methanediamines with oxalyl chloride. Synth. Commun.; 2007; 37, pp. 637-644. [DOI: https://dx.doi.org/10.1080/00397910601055248]

17. Shi, T.; Zerio, C.J.; Sivinski, J.; Ambrose, A.J.; Moore, K.T.; Buckley, T.; Kaneko, L.; Zhang, M.; Zhang, D.D.; Chapman, E. A one-step, atom economical synthesis of thieno[2,3-d]pyrimidin-4-amine derivatives a four-component reaction. Eur. J. Org. Chem.; 2019; 2019, pp. 3269-3272. [DOI: https://dx.doi.org/10.1002/ejoc.201900414] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31857792]

18. Marzona, M.; Carpignano, R. Condensation of heterocyclic amines with formaldehyde. IV. Ann. Chim.; 1965; 55, pp. 1007-1013.