Abstract
Derivatives of a new heterocyclic system, pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine 3, were prepared by sequential treatment of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 1 with 4,5-dihydrothiazol-2-amine 2 and various secondary amines. Single crystal X-ray analysis confirmed the structure of the regioisomer 3. The photophysical characterization of these new compounds was performed by UV/VIS absorption and fluorescence emission spectroscopy. Out of six derivatives studied, only four products 4a–d showed relatively strong fluorescence intensity. The relevant photophysical parameters for all derivatives in this series, including quantum yields and Stokes shifts for the best fluorophores are given.
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Introduction
Pyrimidopyrimidines as an important fused heterocyclic system have interested a great concern due to their wide range of biological activities [1–3]. The literature surveys revealed us they have been used as antitumor [4], antiviral [5], antifungal [6], antimicrobial [7] and antiplatelet [8] agents along with potent inhibitors of the tyrosine kinase domain of epidermal growth factor receptor [9] and 5-phosphoribosyl-1-pyrophosphate synthetase [10]. The [3 + 3] ring closure of 2-aminopyrimidines with a variety of bifunctional electrophiles [11, 12] as well as the treatment of 4,6-dichloro-5-formylpyrimidine with primary amines and aldehydes [13] are the most common synthetic pathways to pyrimidopyrimidines.
In addition, thaizolopyrimidines have been reported to display a range of significant biological properties such as calcium channel and CXCR2 receptor antagonists [14], antitumor, antimetastatic and antiinflammatory agents [15]. The synthesis of thaizolopyrimidines have been achieved via the reaction of 2-thiouracil with ethyl γ-chloroacetoacetate [16] or 1,2-dibromoethane [17] and intramolecular cyclization of 1-(2-hydroxyethyl)-thiouracil with mesyl chloride [18]. The other strategies involve the cyclization of 2-amino-2-thiazoline with ethoxymethylenemalonic esters [19], diketenes [20], acetylene dicarboxylic esters [21] and ethyl malonyl chlorides [22].
In conjunction with our previous work based on the synthesis of new heterocyclic compounds with interesting pharmacological and fluorescent properties [23–26], we wish to report the synthesis of several derivatives of pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine as a novel heterocyclic system together with evaluation of their photophysical properties through their UV/Vis absorption and fluorescence emission spectra.
Experimental
Melting points were taken on an Electrothermal type 9200 melting point apparatus and are uncorrected. The IR spectra were obtained in KBr disks on an Avatar 370 FT-IR Thermo-Nicolet spectrometer (νmax in cm−1). The 1H NMR spectra were recorded on a Bruker AC at 300 MHz using tetramethylsilane (TMS) as an internal reference. Chemical shift values were given in ppm downfield from TMS. The Mass spectra were obtained on a Varian Mat CH-7 instrument at 70 eV. Elemental analysis was performed on a Thermo Finnigan Flash EA microanalyzer. A hemisphere of X-ray data was collected on a Bruker D8 Venture Photon 100 diffractometer using ω scans under control of the APEX2 [27] software package. Raw intensities were reduced to F2 values with SAINT [27] which also performed a global refinement of unit cell parameters. Absorption corrections and merging of equivalent reflections was carried out with SADABS [27] and the structure solved by a combination of Patterson and direct methods (SHELXT [27]). The structure was refined by full-matrix, least-squares methods (SHELX-2014 [28]) with hydrogen atoms attached to carbon placed in calculated positions and that attached to nitrogen placed in a location derived from a difference map and adjusted to give N–H = 0.91 Å. All hydrogen atoms were included as riding atoms with isotropic displacement parameters tied to their attached atoms.
2-(Methylthio)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (3)
To a solution of 2-aminothiazole 1 (1 mmol, 0.1 g) and Et3N (1.5 mmol, 0.2 ml) in CH3CN (10 mL), ethyl 4-chloro-2-(methylthio) pyrimidine-5-carboxylate 2 (1 mmol, 0.23 g) was added. The solution was stirred for 2 h at room temperature. The resulting precipitate was filtered off, washed with water (2 × 50 mL) and dried. Yield =80%, mp = 247–250 °C, 1H NMR (300 MHz, DMSO-d6) δ 2.57 (s, 3H, CH3), 3.64 ppm (t, J = 7.8 Hz, 2H, CH2), 4.58 ppm (t, J = 7.8 Hz, 2H, CH2), 8.98 (s, 1H, CH-pyrimidine). 13C NMR (75 MHz, DMSO) 14.4, 27.0, 49.1, 106.2. 155.3, 158.5, 166.4, 172.5, 176.3. IR (KBr disc, cm−1) ν 3039, 2970, 2929, 1659, 1584. MS (m/z) 252 (M+). Anal. Calcd. for C9H8N4OS2% C, 42.84; H, 3.20; N, 22.21; S, 25.41. Found C, 42.76; H, 3.35; N, 22.12; S, 25.59.
General Procedure for the Preparation of Compounds (4a–f)
The appropriate secondary amine (30 mmol) was added to a stirred mixture of compound 3 (1 mmol, 0.25 g) in acetonitril (10 mL), and the solution was heated under reflux for 3 h. The progress of the reaction was monitored by TLC using CHCl3:MeOH (20:1). The solid obtained on cooling was filtered and recrystallized from ethanol.
2-(Pyrrolidin-1-yl)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4a)
White powder, yield =55%, mp = 294–298 °C, 1H NMR (300 MHz, DMSO-d 6 ) δ 1.96 (m, 4H, 2CH2), 3.48 (m, 6H, 2CH2N and 2CH2), 4.47 (t, J = 7.2 Hz, 2H, 2CH2), 8.78 ppm (s, 1H, pyrimidine). 13C NMR (75 MHz, DMSO) 26.7, 43.9, 46.1, 48.7, 100.8. 156.5, 160.6, 161.3, 166.6, 171.1. IR (KBr disc) ν 3132, 3088, 2958, 2873, 1677, 1586 cm−1. MS (m/z) 275 (M+). Anal. Calcd. for C12H13N5OS % C, 52.35; H, 4.76; N, 25.44; S, 11.64. Found C, 52.22; H, 4.89; N, 25.46; S, 11.94.
2-(Piperidin-1-yl)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4b)
White powder, yield =73%, mp. = 147–150 °C, 1H NMR (300 MHz, DMSO-d 6 ) δ 1.56 (m, 2H, CH2), 1.67 (m, 4H, 2CH2), 3.57 (t, J = 7.5 Hz, 2H, 2CH2), 3.85 (m, 4H, 2CH2N), 4.47 (t, J = 7.2 Hz, 4H, 2CH2), 8.76 ppm (s, 1H, pyrimidine). 13C NMR (75 MHz, DMSO) 22.4, 25.8, 26.7, 45.0, 48.7, 100.3, 156.5, 160.5, 166.4, 170.9, 172.5. IR (KBr disc) ν 3005, 2933, 2855, 1653 cm−1. MS (m/z) 289 (M+). Anal. Calcd. for C13H15N5OS % C, 53.96; H, 5.23; N, 24.20; S, 11.08. Found C, 53.99; H, 5.42; N, 24.57; S, 11.20.
2-(4-Methylpiperidin-1-yl)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4c)
White powder, yield =68%, mp. = 200–202 °C, 1H NMR (300 MHz, DMSO-d 6 ) δ 0.93 (d, J = 5.7 Hz 3H, CH3), 1.08 (m, 2H, CH2) 1.72 (m, 3H, CH2 and CH), 2.98 (t, J = 12 Hz, 2H aqvatorial, CH2), 3.57 (t, J = 7.5 Hz, 2H, CH2), 4.46 (t, J = 7.2 Hz, 2H, CH2), 4.76 (m, axial 2H, CH2N), 8.75 ppm (s, 1H, pyrimidine). 13C NMR (75 MHz, DMSO) 22.0, 26.7, 30.8, 34.0, 44.3, 48.7, 100.4, 156.5, 160.5, 161.2, 166.5, 170.9. IR (KBr disc) ν 3003, 2950, 2911, 2865, 1668, 1610 cm−1. MS (m/z) 303 (M+). Anal. Calcd. for C14H17N5OS % C, 55.43; H, 5.65; N, 23.08; S, 10.57 Found C, 55.59; H, 5.55; N, 23.34; S, 10.25.
2-Morpholino-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4d)
White powder, yield =79%, mp = 285–290 °C, 1H NMR (300 MHz, DMSO-d 6 ) δ 3.35 (t, J = 7.5, 2H, CH2), 3.68 (t, 4H, J = 5.1 Hz, 2CH2N), 3.86(m, 4H, 2CH2O), 4.49 ppm (t, 2H, J = 7.5, CH2); 8.81 ppm (s, 1H, pyrimidine). 13C NMR (75 MHz, DMSO) 26.7, 44.5, 48.7, 66.3, 101.0, 151.4, 156.5, 160.6, 166.5, 171.2. IR (KBr disc) ν 3182, 3076, 2962, 2921, 2859, 1705, 1660 cm−1. MS (m/z) 291 (M+). Anal. Calcd. for C12H13N5O2S % C, 49.47; H, 4.50; N, 24.04; S, 11.00. Found C, 49.41; H, 4.72; N, 24.26; S, 11.16.
2-(4-Methylpiperazin-1-yl)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4e)
White powder, yield =68%, mp = 249–250 °C, 1H NMR (300 MHz, DMSO-d 6 ) δ 2.23 (s, 3H, CH3), 2.39 (m, 4H, CH2-N), 3.58 (t, J = 7.5 Hz, 2H, CH2), 3.78 (m, 4H, 2CH2N), 4.49 (t, J = 7.5 Hz, 2H, CH2), 8.79 ppm (s, 1H, pyrimidine). 13C NMR (75 MHz, DMSO) 26.5, 44.8, 48.7, 51.9, 52.5, 100.9, 156.5, 160.5, 161.3, 166.3, 171.0. IR (KBr disc) ν 3015, 2949, 2864, 2798, 1640, 1608 cm−1. MS (m/z) 304 (M+). Anal. Calcd. for C13H16N6OS % C, 51.30; H, 5.30; N, 27.61; S, 10.53 Found C, 51.63; H,5.50; N, 27.35; S, 10.37.
2-(4-Ethylpiperazin-1-yl)-7,8-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one (4f)
White powder; yield: 78%; mp = 246–248 °C; 1H NMR (300 MHz, , DMSO-d 6 ): δ 1.04 (t, J = 7.2 Hz, 3H, CH3), 2.37 (q, J = 7.2 Hz, 2H, CH2), 2.45 (m, 4H, CH2-N), 3.58 (t, 2H, J = 7.2 Hz, CH2-N), 3.87 (m, 4H, CH2-N), 4.49 (t, 2H, J = 7.2 Hz, CH2),8.79 (s, 1H, pyrimidine).13C NMR (75 MHz, DMSO) 12.3, 26.7, 44.1, 48.7, 51.9, 52.5, 100.8. 156.5, 160.5, 161.3, 166.5, 171.1. IR (KBr disc) ν 3019, 2966, 2937, 2831, 1652, 1609 cm−1. MS (m/z) 318 (M+). Anal. Calcd. for C14H18N6OS % C, 52.81; H, 5.70; N, 26.40; S, 10.07 Found C, 52.72; H, 5.75; N, 26.25; S, 10.12.
Results and Discussion
Chemistry
The presence of two electron-enriched positions in 2-aminothiazoline ring 1 was led to the reaction of this compound with electrophiles either at the exocyclic or endocyclic nitrogen atom depending on the electrophile and reaction conditions [29, 30]. Furthermore, ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 2, which was prepared according to the reported procedure [31], possesses two possible leaving groups, namely Cl and OEt, in which the chlorine atom has been reported to be more reactive than ethoxy moiety [32, 33].
Treatment of 1 with 2 in the presence of Et3N in CH3CN may lead to the synthesis of two possible regioisomers 3 and 3′ as depicted in Fig. 1. The experimental and spectral data showed the formation of only one product with no producing any isolable intermediate. The 1H NMR spectrum of the product displayed a singlet signal at δ 2.51 ppm for the methyl group, two triplet signals at δ 3.64 and 4.58 for the hydrogens of thiazoline ring and a sharp singlet signal at 8.98 ppm belonging to the hydrogen of the pyrimidine moiety. The 13C NMR spectrum also clearly showed nine resolved signals for the corresponding carbons of the compound. The IR spectrum of the product did not exhibit any bands of the starting materials (NH2 and ester groups at 3389, 3419 and 1734, respectively) and the mass spectrum also showed the molecular ion peak at m/z 252 (M+) indicating the molecular formula of C9H8N4OS2.
Scheme for synthesis compound of 2-(methylthio)-8,9-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one
The ambiguity in the structure of the product can be clearly resolved through single crystal X-ray analysis (deposition no. CCDC 1442522) (Figs. 2, 3 and 4).
ORTEP view of compound 3. The displacement ellipsoids are shown at the 50% probability level
Packing of compound 3 viewed down the c axis
Packing of compound 3 viewed approximately along (110)
The single crystal X-ray crystallographic data clearly demonstrates the occurrence of nucleophilic substitution on precursor 2 with 4,5-dihydrothiazol-2-amine 1 through path I in Fig. 1 along with the subsequent cyclization reaction to give product 3.
Upon on the regiochemistry of the product, it appears that the endocyclic amino group of 2-aminothiazole 1 is more nucleophilic than the other amino group and attacks the more electrophilic C-Cl bond on precursor 2 which is followed by an intramolecular acyl nucleophilic substitution on COOEt fragment to form the final product 3. Then, the treatment of compound 3 with various cyclic secondary amines afforded the corresponding products 4a–f (Fig. 5).
Scheme for synthesis derivatives of 2-amino-8,9-dihydro-5H-pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one
The structures of compounds 4a–f have been confirmed by their spectral data. For example, the 1H NMR spectrum of 4d showed two triplet signals at δ 3.68 and 3.86 ppm corresponded to the hydrogens of the morpholine moiety, two triplet signals at δ 3.35 ppm and 4.49 ppm for the hydrogens of the thiazoline core and a sharp singlet peak at 8.81 ppm assigned to the hydrogen of the pyrimidine core. The 13C NMR spectrum clearly showed four resolved signals at 26.8, 44.5, 48.7 and 66.3 ppm for the aliphatic carbons of compound 4d and the other six signals at 101.0, 151.4, 156.5, 160.6, 166.5, 171.2 ppm were assigned to the aromatic carbons. The mass spectrum of compound 4d also showed the molecular ion peak at m/z 291 (M+) indicating the molecular formula of C12H13N5O2S.
Photophysical Study
The design and synthesis of selective and sensitive compounds containing the pyrimidine moiety with fluorescent probes are attractive research topics in the fields of optoelectronics [34], chemosensors and molecular imaging owing to their biological and environmental interest [35, 36]. Fluorescent probes are the important instrumentation in gaining insight into cellular and bacterial environments [37, 38], and fluorescence spectroscopy is one of the most useful techniques to probe the binding of liposomes to proteins, DNA, and other biomolecules in chemical biology [39, 40]. Herein, we describe the evaluation of these new fluorescent pyrimidine analogs and provide their structure-photophysical properties relationships.
The absorption spectrum of 4c was scanned in CH3CN (5 × 10−5 M) and shown in Fig. 6. The wavelengths of maximum absorption (λmax) were in 275 and 340 nm but the highest emission was observed when the compound was excited in 340 nm.
UV/Vis Absorption spectrum of compound 4c in dilute CH3CN solution (2 × 10−5 M)
All the absorption and emission spectra of compounds 4a–f were recorded in CH3CN, and their λmax and λflu values were compiled in Table 1.
Values of the extinction coefficient (ε) were calculated as the slope of the plot of absorbance υs. concentration and had a precision on the order of 5%. The fluorescence quantum yield (Φ) which is the ratio of photons absorbed to photons emitted through fluorescence relative to fluorescein as the reference compound were calculated according to the literature [41]. (Table 1) Compounds 4a–d exhibited moderately good fluorescence quantum yields. The highest value was obtained for compound 4c (Φ = 0.80). The compounds under this study exhibited the stokes shifts ranging from 70 to 95 nm that was calculated from the difference between absorption and emission maxima in cm−1 [42].
Photophysical data in Table 1 demonstrated that all compounds were neutral, uncharged, highly fluorescent molecules that were absorbed with high extinction coefficients and emitted at around 410–425 nm. Compounds like biogenic amines are markers for many processes, e.g. recognition of cancer, so that their detection and determination are important [43, 44]. Amines which do not posses an aromatic system can not be detected directly by UV absorption or fluorescence. For determination of these compounds, especially at low concentrations, many fluorogenic reagents have been developed [45–47]. Moreover, the known fluorescence and pharmacological properties of pyrimidine [48, 49] and thiazole moieties [50–52] as well as the factors promoting proliferation in the biological and photophysical properties and possible relationship between these substances [53] were persuaded us to synthesize thiazolopyrimidine derivatives and study their fluorescence properties. For this purpose, the thiomethyl derivative 3 was converted into products 4a–f, and speculates that the presence of amino group at the 2-position in pyrimidothiazolopyrimidine plays an important role in the aforementioned strong fluorescence. Compounds 4a–d, which have morpholine, pyrrolidine, piperidine or 4-methylpiperidine group at the 2-position of the pyrimidine ring, showed stronger fluorescence intensity than did the precursor 3 with methylsulfanyl group. Compounds 4e and 4f showed very weak fluorescence intensities. (Fig. 7) This could mean that a new or extended planar system with enhanced delocalization of π-bonding has been formed.
Emission spectrum of compounds 4a–f at λex 330–340 nm in dilute CH3CN solution (2 × 10−7 M)
The emission spectra of chemical compounds can be affected by the medium and they can bring about a change in the position, intensity, and shape of absorption bands [54]. Photophysical properties of 4c have been studied in a number of organic solvents and H2O. Fig. 8 shows the emission spectra of 4c in CHCl3, DMF, THF, MeCN, MeOH, EtOH, and H2O. The fluorescence intensity maxima were found to vary with the nature of the solvent which can be attributed to solvatochromic properties [55]. As can be seen, aprotic solvents such as CHCl3, DMF, THF and MeCN showed the higher emission value in comparison with the protic ones. The aprotic solvents do not have hydrogen bond with the solute and the spectrum of the solute closely approximates the spectrum that would be produced in the gaseous state, in which fine structure is often observed. In protic solvents, hydrogen bond forms a solute-solvent complex and the fine structure may disappear [56].
Fluorescence intensity of a solution of compound 4c (2 × 10−7 M) in the solvents DMF, CHCl3, CH3CN, THF, EtOH, MeOH and H2O at λex. = 340 nm
Conclusion
In summary, we have described the synthesis of various derivatives of the new heterocyclic system, pyrimido[5,4-e]thiazolo[3,2-a]pyrimidin-5-one via sequential treatment of ethyl 4-chloro-2-(methylthio)pyrimidine-5-carboxylate 1 with 4,5-dihydrothiazol-2-amine 2 and subsequently with secondary amines to obtain products 4a–f. An account on the single crystal X-ray analysis of the product 3 along with the photophysical properties of the corresponding substituted derivatives 4a–f was given. Due to their interesting fluorescence properties, these new heterocyclic pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine derivatives can be used as fluorescent markers and probes for studies in biochemistry and pharmacology.
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Acknowledgements
The authors gratefully acknowledge Ferdowsi University of Mashhad for financial support of this project. (3/25439). JTM acknowledges the support of the NSF-MRI program (grant No. 1228232) for the purchase of the diffractometer and Tulane University for support of the Tulane Crystallography Laboratory.
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Ebrahimpour, Z., Bakavoli, M., Shiri, A. et al. Synthesis, X-ray and Fluorescence Characteristics of Pyrimido[5,4-e]thiazolo[3,2-a]pyrimidine as a Novel Heterocyclic System. J Fluoresc 27, 1183–1190 (2017). https://doi.org/10.1007/s10895-017-2055-9
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DOI: https://doi.org/10.1007/s10895-017-2055-9