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5-[(Z)-5-Chloro-2-oxoindolin-3-ylidene]-3-{(E)-[(4-hydroxyphenyl)imino]methyl}-2-thioxothiazolidin-4-one

Molbank 2019, 2019(2), ; https://doi.org/10.3390/M1063

Communication
(E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxy-phenyl)-6-((E)-2,5-dimethoxystyryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]}prop-2-en-1-one and (E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]}prop-2-en-1-one
1
Department of Chemistry, Faculty of Science and Technology–Airlangga University, Surabaya 60115, Indonesia
2
Department of Chemical Engineering, State Polytechnic of Samarinda, Samarinda 75131, Indonesia
3
Department of Chemistry, Tadulako University, Palu 94118, Indonesia
*
Author to whom correspondence should be addressed.
Received: 5 May 2019 / Accepted: 30 May 2019 / Published: 4 June 2019

Abstract

:
Dihydropyrimidine derivatives possess great potential to be used as a precursor for the synthesis of wide diverse dihydropyrimidine-like derivatives. In this research, the title compounds were synthesized through the reaction between 5-acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione and 2,5-dimethoxybenzladehyde under aldol condensation condition. The title compound, (E)-3-(2,5-dimethoxyphenyl)-1-{[(4-(2,5-dimethoxyphenyl)-6-((E)-2,5-dimethoxystyryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl)]}prop-2-en-1-one (yield 15%), was obtained as major product, whereas (E)-3-(2,5-dimethoxyphenyl)-1-{[(4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro pyrimidin-5-yl)]}prop-2-en-1-one (yield 8%) as side product through vinylogous aldol condensation.
Keywords:
5-acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione; aldol condensation; vinylogous aldol condensation

1. Introduction

The derivatives of 3,4-dihydropyrimidin-2(1H)-ones (DHPMs) as products of the Biginelli reaction are known to have various pharmacological activities, such as anticancer [1], antioxidant [2], anti-inflammation, antibacterial, and antifungal [3], anti HIV [4], and antihypertensive [5]. The discovery of 4-(3-hydroxyphenyl)-3,4-dihydropyrimidine-2(1H)-thione, which is well known as monastrol (1) as moderate anticancer agent through inhibition of the microtubule-stimulated ATPase activity of Eg5 [6] inspired researchers to use this protein as a protein target to develop new anticancer agents due to its specific function during cell cycle. Replacement of ester group at the 5-position of monastrol with acyl group enhances its potency when compared with the racemic monastrol [7], whereas replacement with cyclohexanone ring (enastron (compound 2) and dimethylenastron (compound 3), Figure 1) significantly increased their inhibitor activity as compared to monastrol [8]. Based on the information, we focus our study on finding anticancer compounds from the 5-acyl-3,4-dihydropyrimidine-2-thione family.
From the organic synthesis point of view, acetyl group at five-position is a potential moiety for introducing the benzylidene group to form a chalcone analogue using aldol condensation, whereas the methyl group of six-position can be transformed into styryl moiety through vinylogous aldol condensation. Compounds with such structure are known for their antimicrobial and cytotoxicity activity, and have already been prepared by the Biginelli reaction using (thio)urea, derivatives of benzaldehyde, and curcumin as 1,3-dicarbonyl component [6]. However, this reaction route required an additional reaction step of curcumin or its derivatives to be prepared. Herein, we reported the synthesis of the 5,6-dibenzylidene DHPM-type (6) and 5-benzylidene DHPM-type (5) employing aldol condensation while using a 5-acetyl-6-methyl DHPM derivative as precursor.

2. Results and Discussion

The synthesis of the title compounds were performed in two steps, firstly the synthesis of a DHPM derivative (compound 4) from acetylacetone, 2,5-dimethoxybenzaldehyde, and thiourea using Biginelli reaction. Compound 4 was then used as a precursor to synthesize the title compounds 5 and 6 by reaction with 2,5-dimethoxybenzaldehyde under aldol condition, as presented in Figure 2.
The synthesis of compound 4 was performed following the previous article [7] with slight modification (differed in purification steps). Compound 4 was then used as precursor to synthesize title compounds 5 and 6 by reaction with 2,5-dimethoxybenzaldehyde under the aldol condition. The reaction progress was monitored by thin layer chromatography (TLC) until completion. During TLC experiment, compound 5 was firstly observed, whereas compound 6 appeared later. At the end of the reaction, only these two spots were observed. This observation supported that the first step reaction is the introduction of the benzylidene moiety on the acetyl group [9]. The crude reaction product was then separated on column chromatography using silica gel as the stationary phase and chloroform: ethyl acetate (10:1) as mobile phase. After separation with column chromatography, we obtained 8% yield for compound 5 and 15% for compound 6.
5-Acetyl-4-(2,5-dimethoxyphenyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-thione (4): colorless needle crystal (481 mg, 80%), Rf 0.48 (n-hexane: ethyl acetate = 2:1); m.p 266–268 °C (EtOH-H2O), HRMS (ESI) [M + Na]+ calcd. for [C15H18N2O3SNa]+ = 329.0936 found = 329.0952, IR (cm−1): 3215 (N-H), 2981 (C-H aromatic), 2833 (aliphatic C-H), 1633 (conjugated C=O), 1573, 1496, 1469 ( aromatic C=C-), 1249 (Caryl-O-Calkyl), 1176 (-C=S); 1H-NMR (400 MHz, CDCl3) δH (ppm) 7.93 (s, 1H), 7.46 (s, 1H), 5.75 (d, J = 3.3 Hz, 1H), 6.84 (d, J = 8.8 Hz, 1H), 6,79 (dd, J = 9.0, 2.9 Hz, 1H), 6.59 (d, J = 3.0 Hz, 1H), 3.86 (s, 3H), 3.72 (s, 3H), 2.40 (s, 3H), 2.04 (s, 3H); 13C-NMR (101 MHz, CDCl3) δH (ppm) 195.8, 174.7, 154.0, 150.6, 143.9, 129.0, 114.4, 113.2, 111.5, 108.0, 56.0, 55.8, 50.9, 29.5, 19.3.
The mass determination of compound 4 exhibited [M + Na]+ ion at m/z 329.0952, which closed to the theoretical value of 329.0936 and was suitable for the molecular formula of C15H18N2O3SNa (Supplementary Figure S1). The analysis of IR spectra showed the existence of N-H amide, C-H aromatic, C-H aliphatic, conjugated C=O, C=C aromatic, Calkyl-O-Caryl ether, and C=S bonds, which were consecutively indicated by bands at (cm−1) 3215, 2981, 2833, 1633, 1573–1469, 1249, and 1176 [10] (Supplementary Figure S2). The nuclear magnetic resonance (NMR) data of compound 4 are presented in Table 1. The existence of the dihydropyrimidine ring was assigned by following signals: proton signal of chiral C-4 at δH 5.75 ppm (d, 3JHH = 3.3 Hz, 1H), proton of N-3 at δH 7.46 ppm (s, 1H), proton of N-1 at δH 7.93 ppm (s, 1H), and 13C signal of C-5 and C-6 at δC at 108.0 ppm and 143.9 ppm. The acetyl group was assigned by methyl signal at δH 2.40 ppm (s, 3H) and carbonyl signal at δC 195.8 ppm, while the methyl group at C-7 appeared as single signal at δH 2.04 ppm. Three aromatic proton signals with ABX system were assigned, as follows: one aromatic proton with ortho and meta coupling (δH 6.79 ppm (dd, J = 9.0 and 2.9 Hz, 1H)), one aromatic proton with ortho coupling (δH 6.84 ppm (d, J = 8.8 Hz, 1H)), and one aromatic proton with meta coupling (δH 6.59 ppm (d, J = 3.0 Hz, 1H)). Two methoxy groups appeared at δH 3.86 ppm (s, 3H) and δH 3.72 ppm (s, 3H) (Supplementary Figure S3 for 1H-NMR and Supplementary Figure S4 for 13C-NMR).
(E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]}prop-2-en-1-one (5). Yellow needle crystal (38 mg, 8%); m.p 154–156 °C (EtOH-H2O); UV-Vis (Et-OH) λmax (nm) 298 (log ɛ = 3.98); 372 (log ɛ = 3.98) (Supplementary Figure S5); HRMS (ESI): calcd. for [C24H26N2NaO5S]+ = 477.1460 found = 477.1457; IR (cm−1): 3174 (N-H), 3005 (aromatic C-H), 2978 (aliphatic C-H), 1680 (conjugated C=O), 1645 (conjugated C=C), 1580, 1493, 1427 (aromatic C=C), 1279 (Calkyl-O-Caryl), 1173 (C=S). 1H-NMR (400 MHz, Acetone-d6) δH (ppm): 9.19 (s, 1H), 8.30 (s, 1H), 7.77 (d, J = 15.8 Hz, 1H), 7.18 (d, J = 15.7 Hz, 1H), 7.13 (d, J = 2.6 Hz, 1H), 6.97–6.94 (m, 2H), 6.84 (d, J = 3.1 Hz, 1H), 6.83–6.79 (m, 2H), 5.92 (d, J = 3.4 Hz, 1H), 3.84 (s, 3H), 3.81 (s, 3H), 3.77 (s, 3H), 3.69 (s, 3H), 2.46 (s, 3H). 13C-NMR (101 MHz, Acetone-d6) δC (ppm): 189.05, 176.64, 154.80, 154.62, 153.89, 151.48, 143.63, 137.41, 132.08, 126.76, 125.26, 117.76, 115.29, 113.97, 113.66, 113.54, 112.86, 110.86, 56.44, 56.39, 56.04, 55.79, 51.28, 18.41.
(E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxy-phenyl)-6-((E)-2,5-dimethoxystyryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]}prop-2-en-1-one (6): Yellow needle crystal (90 mg, 15%); m.p 212–214 °C (EtOH-H2O); UV-Vis (EtOH) λmax (nm) 291 (log ɛ = 4.44), 389 (log ɛ = 4.21) (Supplementary Figure S12); HRMS (ESI): calcd. for [C33H34N2NaO7S]+ = 625.1984 found = 625.1981; IR (cm−1): 3198 (N-H), 2945 (aliphatic C-H), 1624 (conjugated C=O), 1578, 1562, 1495 (aromatic C=C), 1276 (Calkyl-O-Caryl), 1225 (C=S). 1H-NMR (400 MHz, DMSO-d6) δH (ppm): 10.36 (d, J = 1.1 Hz, 1H), 9.41 (dd, J = 3.8, 1.4 Hz, 1H), 7.59 (d, J = 15.8 Hz, 1H), 7.43 (d, J = 16.4 Hz, 1H), 7.37 (d, J = 16.4 Hz, 1H), 7.25 (d, J = 15.8 Hz, 1H), 7.11 (d, J = 3.0 Hz, 1H), 7.10 (d, J = 2.7 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 6.95–6.93 (m, 3H), 6.89 (dd, J = 9.0, 3.0 Hz, 1H), 6.85 (dd, J = 8.9, 3.1 Hz, 1H), 6.70 (d, J = 3.0 Hz, 1H), 5.59 (d, J = 4.0 Hz, 1H), 3.73 (s, 3H), 3.69 (s, 3H), 3.68 (s, 3H), 3.66 (s, 3H), 3.64 (s, 3H), 3.60 (s, 3H). 13C-NMR (101 MHz, DMSO-d6) δC (ppm): 188.66, 175.10, 153.21, 153.10, 153.04, 152.41, 151.73, 150.33, 141.15, 135.04, 131.76, 130.79, 127.05, 124.94, 123.61, 120.65, 117.48, 116.07, 114.06, 112.93, 112.88, 112.56, 112.32, 112.31, 112.26, 112.18, 55.91, 55.90, 55.85, 55.33, 55.32, 55.29, 49.91.
Numbering of the molecular structure and selected HMBC correlation of compound 5 are presented in Figure 3, and in Figure 4 for compound 6. Mass determination of compounds 5 and 6 showed [M + Na]+ ion at m/z 477.1457 for compound 5 (Supplementary Figure S6) and m/z 625.1981 for compound 6 (Supplementary Figure S13), respectively, which were closed to the theoretical value of 477.1460 and 625.1984. Infrared spectra of both compounds 5 and 6 showed vibration bands of N-H amide, C-H aliphatic, conjugated C=O, C=C aromatic, Calkyl-O-Caryl, and C=S bonds consecutively at wave numbers (cm-1): 3174, 2978, 1680 1580, 1279, and 1173 for compound 5 (Supplementary Figure S7), and 3198, 2945, 1624, 1578, 1276, and 1225 for compound 6 (Supplementary Figure S14). The existence of two alkene groups with the trans configuration of compound 6 were assigned by four doublet proton signals at chemical shift of δH 7.59 and 7.25 ppm (J = 15.8 Hz) and signals at δH 7.43 and 7.37 ppm (J = 16.4 Hz) (Supplementary Figure S15), whereas the existence of an alkene group in compound 5 was assigned by two doublet proton signals at δH 7.77 and 7.18 ppm (J = 15.8 Hz) (Supplementary Figure S8).
Two-dimensional NMR experiments (Heteronuclear Multiple Quantum Coherence (HMQC) and Heteronuclear Multiple Bond Correlation (HMBC)) were performed to prove that aldol condensation proceeded at C-8. The methyl olefinic fragment at δH 2.46 ppm proceeded a long range correlation with carbon signal at C 110.86 ppm (C-5) and 143.63 ppm (C-6) (Compound 5). The HMBC correlation tables of compounds 5 and 6 are presented in Table 2, Table 3, respectively. The 13C-NMR spectra of compound 5 exhibited 24 signals that represented all carbon atoms of compound 5 (Supplementary Figure S9), while the 13C-NMR spectra of compound 6 showed 33 signals reflected all the carbon atoms of compound 6 (Supplementary Figure S16). The structures of compounds 5 and 6 are consistent with the molecular mass.

3. Materials and Methods

3.1. General

The chemicals were provided from the commercial sources with pro analysis or pro synthesis grade and were used without prior purification. Thin layer chromatography was conducted on silica gel GF254 plate (E Merck, Darmstadt, Germany) for the monitoring of the reaction progress and test of purity. The spots of TLC were identified by UV lamp (λ 254 nm). The UV spectrum was recorded on a UV-Vis spectrophotometer type UV-1800 (Shimadzu, Kyoto, Japan). The mass spectra were measured on a HRESIMS QTOF micrOTOF-Q II Bruker Daltonics (Billerica, MA, USA). The Fourier transform infrared (FTIR) spectrum was recorded on an IRTracer100 spectrophotometer (Shimadzu, Kyoto, Japan) while using the diffuse reflectance method. The nuclear magnetic resonance (NMR) spectrum (1H-, and 13C-APT) was recorded on a JEOL JNM-ECS400 spectrometer (at 400 and 100 MHz) (JEOL Ltd., Tokyo, Japan), with Acetone-d6, CDCl3 and DMSO-d6 as the solvent and internal standard.

3.2. Synthesis of Compound 4

In a screw-capped vial, the mixture of 2,5-dimethoxybenzaldehyde (0.331 g, 2 mmol), acetyl acetone (0.2 g, 2 mmol), and thiourea (0.19 g, 2.5 mmol) was heated without stirring at 110 °C for 3 h [7]. The reaction mixture was then allowed to cool to room temperature, dissolved in ethanol, then added with water dropwise, and the precipitate was filtered off. The solid was then recrystallized using aqueous ethanol.

3.3. Synthesis of the Title Compounds

Compound 4 (0.306 g, 1 mmol), 2,5-dimethoxybenzaldehyde (0.414 g, 2.5 mmol), KOH (0.056 g, 1 mmol), and ethanol (10 mL) were placed in a three neck round bottom flask that was equipped with a reflux condenser. The reaction mixture was refluxed at 50 °C for 11 h and then cooled to room temperature. The reaction mixture was poured to ice-water, neutralized with HCl-ethanolic solution, and the precipitate was filtered off. The crude product was then subjected to a silica gel column chromatography while using n-hexane:ethyl acetate (10:1) as eluent to furnish the title compounds (compounds 5 and 6).

4. Conclusions

In conclusion, we have synthesized two new compounds (E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxyphenyl)-6-methyl-2-thioxo-1,2,3,4-tetrahydro-pyrimidin-5-yl]}prop-2-en-1-one (compound 5) and (E)-3-(2,5-Dimethoxyphenyl)-1-{[4-(2,5-dimethoxy-phenyl)-6-((E)-2,5-dimethoxystyryl)-2-thioxo-1,2,3,4-tetrahydropyrimidin-5-yl]}prop-2-en-1-one (compound 6) under aldol condensation condition.

Supplementary Materials

FTIR, HRMS (ESI), 1H-NMR and 13C-APT-NMR, HMBC and HMQC spectra of the prepared compounds are available on line.

Author Contributions

H.S. brought the idea, managed the research, and prepared the manuscript. N.K., E.S., and Y.A. conducted the experiment, K.U.H. brought the idea and did the structure elucidation, I.I. did structure elucidation, A.N.K. corrected the manuscript.

Funding

This research was funded by Universitas Airlangga through Hibah Riset Mandat 2018 research scheme, grant number of 1919/UN3.1.8/LT/2018.

Acknowledgments

The authors acknowledge Lembaga Penelitian dan Inovasi of Airlangga University for the funding through the Riset Mandat 2018 Research Grant and to the Department of Chemistry–Chulalongkorn University for HRMS analysis.

Conflicts of Interest

The authors declare no conflict of interest.

References

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Figure 1. Replacement of ester group of monastrol (1) with acyl group increases anticancer activity.
Figure 1. Replacement of ester group of monastrol (1) with acyl group increases anticancer activity.
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Figure 2. Synthesis reaction of the title compounds.
Figure 2. Synthesis reaction of the title compounds.
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Figure 3. (a) Numbering of the structure, and (b) selected HMBC correlation for compound 5.
Figure 3. (a) Numbering of the structure, and (b) selected HMBC correlation for compound 5.
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Figure 4. (a) Numbering of the structure, and (b) selected HMBC correlation for compound 6.
Figure 4. (a) Numbering of the structure, and (b) selected HMBC correlation for compound 6.
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Table 1. Nuclear magnetic resonance (NMR) data of compound 4 in CDCl3.
Table 1. Nuclear magnetic resonance (NMR) data of compound 4 in CDCl3.
No. AtomδH (Mult, J Hz)δC (ppm)
17.93 (s, 1H)-
2-174.7
37.46 (s, 1H)-
45.75 (d, J = 3.3 Hz, 1H)50.9
5-108.0
6-143.9
72.04 (s, 3H)19.3
8-129.0
9-154.0
9-OMe3.86 (s, 3H)56.3
106.84 (d, J = 9.0 Hz, 1H)114.4
116.79 (dd, J = 9.0, 3.0 Hz, 1H)113.2
12-150.6
12-OMe3.72 (s, 3H)55.8
136.59 (d, J = 3.0 Hz, 1H)111,5
14-195.8
152.40 (s, 3H)29.5
Table 2. NMR data of compound 5 in Acetone-d6.
Table 2. NMR data of compound 5 in Acetone-d6.
No. AtomδH (ppm), mult, J (Hz)δC (ppm)HMBC
19.19 (s, 1H) C-5
2 176.64
38.30 (s, 1H)
45.92 (d, J = 3.4 Hz, 1H)51.28C-2, C-5, C-6, C-8 C-17, C-18, C-22
5 110.86
6 143.63
72.46 (s, 3H)18.41C-5, C-6
8 189.05
97.18 (d, J = 15.8 Hz, 1H)126.76C-11
107.77 (d, J = 15.8 Hz, 1H)137.41C-8, C-9, C-12, C-16
11 125.26
12 153.89
12-OCH33.81 (s, 3H)56.39C-12
136.83–6.79 (m, 2H)113.54
146.83–6.79 (m, 2H)117.76
15 154.62
15-OCH33.77 (s, 3H)56.04C-15
167.13 (d, J = 2.6 Hz, 1H)113.97C-10, C-12, C-14
17 132.08
18 151.48
18-OCH33.84 (s, 3H)56.44C-18
196.97–6.94 (m, 2H)112.86
206.97–6.94 (m, 2H)113.66
21 154.80
21-OCH33.69 (s, 3H)55.79C-21
226.84 (d, J = 3.1 Hz, 1H)115.29C-18, C-20, C-21
Table 3. NMR data of compound 6 in DMSO-d6.
Table 3. NMR data of compound 6 in DMSO-d6.
No. AtomδH (ppm), mult, J (Hz)δC (ppm)HMBC
110.36 (d, J = 1.4 Hz, 1H) C-2, C-5, C-6, C-7
2 175.10
39.41 (dd, J = 4.0, 1.4 Hz, 1H) C-2, C-5
45.59 (d, J = 4.0 Hz, 1H)49.91C-2, C-5, C-6, C-15, C-24, C-25
5 112.18
6 141.15
77.37 (d, J = 16.4 Hz, 1H)120.65C-6, C-8, C-9
87.43 (d, J = 16.4 Hz, 1H)131.76C-6, C-7, C-10
9 124.94
10 151.73
10-OCH33.69 (s, 3H)55.33C-10
116.95–6.93 (m, 3H) 112.88
126.89 (dd, J = 9.0, 3.0 Hz, 1H)116.07C-10
13 153.10
13-OCH33.64 (s, 3H)55.90C-13
147.11 (d, J = 3.0 Hz, 1H)112.31C-8, C-10, C-12
15 188.66
167.25 (d, J = 15.8 Hz, 1H)127.05C-15, C-18
177.59 (d, J = 15.8 Hz, 1H)135.04C-15, C-16, C-19
18 123.61
19 152.41
19-OCH33.68 (s, 3H)55.85C-19
206.95–6.93 (m, 3H)112.93
216.95–6.93 (m, 3H)117.48
22 153.21
22-OCH33.60 (s, 3H)55.91C-22
237.10 (d, J = 2.7 Hz, 1H)112.26C-17, C-21, C-25
24 130.79
25 150.33
25-OCH33.73 (s, 3H)55.29C-25
266.97 (d, J = 8.8 Hz, 1H)112.56
276.85 (dd, J = 8.9, 3.1 Hz, 1H)112.32C-25, C-29
28 153.04
28-OCH33.66 (s, 3H)55.32C-28
296.70 (d, J = 3.0 Hz, 1H)114.06C-25, C-27

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