Solvent-free synthesis of substituted thiopyrans <i>via</i> multicomponent reactions of <i>α</i>-haloketones

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Fatemeh Sheikholeslami-Farahani, Zinatossadat Hossaini, Faramarz Rostami-Charati.Solvent-free synthesis of substituted thiopyrans via multicomponent reactions of α-haloketones[J]. Chin. Chem. Lett., 2014,25(01): 152-154 复制到剪切板

Solvent-free synthesis of substituted thiopyrans via multicomponent reactions of α-haloketones

Fatemeh Sheikholeslami-Farahani^a , Zinatossadat Hossaini^b, Faramarz Rostami-Charati^c

* Corresponding authors at:^a Department of Chemistry, Firoozkooh Branch, Islamic Azad University, Firoozkooh, Iran;
^b Department of Chemistry, Qaemshahr Branch, Islamic Azad University, Qaemshahr, Iran;
^c Department of Chemistry, Facualty of Science, Gonbad Kavous University, Gonbad, Iran

Received:2013-9-6, Revised:2013-10-8, online:2013-11-12.

E-mail addresses:sheikholeslami@iaufb.ac.ir

Abstract: A straightforward and efficient method for the synthesis of thiopyran derivatives via three-component reaction of alkyl propiolate, benzoylisothiocyanate or its derivatives and α-haloketones in the presence of triphenylphosphine under solvent-free conditions at 70 ℃ without using any catalyst is reported. The method offers several advantages including high yields of products and an easy work-up procedure.

Key words: Thiopyran Triphenylphosphine α-Haloketones Solvent-free conditions Benzoyl isothiocyanate

1. Introduction

At present, heterocycles with sulfur atoms, like thiopyrans, have attracted increased attention. These compounds have different biological activities ^[1] that have been recognized ^[2]. Thiopyrans are used in medicinal chemistry, but receive relatively less attention ^[3]. Also, thiopyrans are often in the structure of natural products with different pharmaceutical activities such as anti-bacterial ^[4], anti-hyperplasia ^[5], anti-psychiatric ^[6], and anticancer activities ^[7]. Investigation of anticancer activity of thiopyran derivatives showed that they have antiproliferative activity against tumor cell lines ^[8]. It has also been described that substituted thiopyrans are powerful inhibitors of deoxyribonucleic acid-protein kinases ^[9]. However, the methods for synthesis of these important compounds often feature tedious synthetic routes, long reaction time, harsh reaction conditions, and narrow application scope of substrates. In addition, to the best of our knowledge, there have been few reports about the synthesis of thiopyran derivatives ^{[10, 11, 12]}. Hence, we describe herein the reaction of alkyl propiolate 1, benzoylisothiocyanate 2 and ahaloketones 3 in the presence of triphenylphosphine 4 under solvent-free conditions to produce substituted thiopyran derivatives 5 in good yield (Scheme 1).

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Scheme 1.Reaction of propiolates, aroyl isothiocyanates and α-halo carbonyl compounds in the presence of triphenylphosphine.

2. Experimental

All chemicals used in this work were purchased from Fluka (Buchs, Switzerland) and were used without further purification. Melting points were measured on an Electrothermal 9100 apparatus. Elemental analyses for C, H, and N were performed using a Heraeus CHN-O-Rapid analyzer. Mass spectra were recorded on a FINNIGAN-MAT 8430 spectrometer operating at an ionization potential of 70 eV. IR spectra were measured on a Shimadzu IR-460 spectrometer. ¹H NMR and ¹³C NMR spectra were measured with a BRUKER DRX-500 AVANCE spectrometer at 500.1MHz and 125.8 MHz, respectively. ¹H NMR and ¹³C NMR spectra were obtained for solutions in CDCl₃ using TMS as the internal standard or 85% H₃PO4 as the external standard.

General procedure for preparation of compounds 5a-e. α- Haloketones (2-mmol) and triphenylphosphine (2 mmol) were stirred at 70 ℃ for 45 min. After 45 min, triethylamine (2 mmol) and alkyl propiolate (2 mmol) were added to the mixture. Then, arylisothiocyanate (2 mmol) was added after 15 min. The reaction mixture was stirred for 8 h at 70 ℃. After completion of reaction (monitored by TLC), 15 mL H₂O was poured into the reaction mixture, and the solid residue was filtered and washed by cold diethylether (Et₂O) to afford 5.

Methyl 2-(benzoilimino)-6-phenyl-2H-thiopyran-3-carboxylate (5a): Yellow oil, yield: 0.45 g (65%) IR (KBr, cm^-1): υ 1738, 1725, 1695, 1587, 1463, 1348, 1259. ¹H NMR (500.1 Hz, CDCl₃): δ 3.78 (s, 3 H, MeO), 6.37 (d, 1 H, ³J = 7.8, CH), 7.28 (d, 1 H, ³J = 7.8, CH), 7.38 (t, 1 H, ³J = 7.4, CH), 7.56 (m, 3 H, 3 CH), 7.64 (t, 2 H, ³J = 7.8, 2 CH), 7.78 (d, 2H, ³J = 7.6, 2 CH), 8.14 (d, 2 H, ³J = 7.6, 2 CH). ¹³C NMR (125.7 Hz, CDCl₃): δ 52.4 (MeO), 118.6 (C), 128.2 (CH), 129.4 (CH), 130.2 (2 CH), 130.6 (2 CH), 131.4 (2 CH), 131.8 (2 CH), 133.2 (CH), 134.8 (C), 135.4 (C), 141.7 (C), 143.6 (CH), 160.4 (C=O), 162.7 (C=N), 172.4 (C=O). EI-MS: m/z 349 (10, M⁺), 318 (86), 105 (100), 77 (88), 31 (100). Anal. Calcd. for C₂₀H₁₅NO₃S (349.40): C 68.75, H 4.33, N 4.01; found C 68.83, H 4.42, N 4.12%.

Methyl 2-(4-methoxybenzoilimino)-6-(4-methoxyphenyl)-2Hthiopyran- 3-carboxylate (5b): Yellow oil, yield: 0.57 g (70%). IR (KBr, cm^-1): υ 1735, 1728, 1695, 1654, 1588, 1474, 1357. ¹H NMR (500.1 Hz, CDCl₃): δ 3.75 (s, 3 H, MeO), 3.82 (s, 3 H, MeO), 3.87 (s, 3 H, MeO), 6.29 (d, 1 H, ³J = 7.5, CH), 7.12 (d, 2 H, ³J = 7.6, 2 CH), 7.22 (d, 2 H, ³J = 7.6, 2 CH), 7.30 (d, 1 H, ³J = 7.5, CH), 7.62 (d, 2 H, ³J = 7.6, 2 CH), 8.04 (d, 2 H, ³J = 7.6, 2 CH). ¹³C NMR (125.7 Hz, CDCl₃): δ 51.8 (MeO), 54.5 (MeO), 55.2 (MeO), 115.4 (2 CH), 116.5 (2 CH), 118.3 (C), 128.5 (CH), 129.4 (C), 130.4 (2 CH), 131.2 (2 CH), 142.7 (C), 145.2 (CH), 158.3 (C), 161.4 (C=O), 162.5 (C=N), 164.7 (C), 171.9 (C=O). Anal. Calcd. for C₂₂H₁₉NO₅S (409.45): C 64.54, H 4.68, N 3.42; found: C 64.63, H 4.76, N 3.54%.

Methyl 2-(4-methoxybenzoilimino)-6-(4-methylphenyl)-2H-thiopyran- 3-carboxylate (5c): Yellow oil, yield: 0.61 g (78%). IR (KBr, cm^-1): υ 1732, 1712, 1687, 1646, 1547, 1485, 1362, 1295. ¹H NMR (500.1 Hz, CDCl₃): δ 2.36 (s, 3 H, Me), 3.78 (s, 3 H, MeO), 3.85 (s, 3 H, MeO), 6.19 (d, 1H, ³J = 7.4, CH), 7.23 (d, 2 H, ³J = 7.8, 2 CH), 7.34 (d, 1 H, ³J = 7.5, CH), 7.38 (d, 2 H, ³J = 7.5, 2 CH), 7.58 (d, 2 H, ³J = 7.6, 2 CH), 8.14 (d, 2 H, ³J = 7.6, 2 CH). ¹³C NMR (125.7 Hz, CDCl₃): δ 22.3 (Me), 51.8 (MeO), 55.4 (MeO), 114.8 (2 CH), 117.8 (C), 127.4 (CH), 129.6 (2 CH), 130.2 (C), 131.4 (2 CH), 132.3 (2 CH), 133.7 (C), 137.6 (C), 141.6 (C), 144.8 (CH), 161.7 (C=O), 162.8 (C=N), 163.8 (C), 175.4 (C=O). Anal. Calcd. for C₂₂H₁₉NO₄S (482.50): C 67.16, H 4.87, N 3.56; found: C 67.04, H 4.76, N 3.45%.

Methyl 2-(4-methylbenzoilimino)-6-(4-bromophenyl)-2H-thiopyran- 3-carboxylate (5d): Yellow oil, yield: 0.66 g (75%). IR (KBr, cm^-1): υ 1732, 1715, 1695, 1648, 1537, 1465, 1374, 1283. ¹H NMR (500.1 Hz, CDCl₃): δ 2.38 (s, 3 H, Me), 3.82 (s, 3H, MeO), 6.23 (d, 1H, ³J = 7.6, CH), 7.35 (d, 1 H, ³J = 7.6, CH), 7.43 (d, 2 H, ³J = 7.6, 2 CH), 7.58 (d, 2 H, ³J = 7.8, 2 CH), 7.63 (d, 2 H, ³J = 7.6, 2 CH), 7.86 (d, 2 H, ³J = 7.8, 2 CH). ¹³C NMR (125.7 Hz, CDCl₃): δ 22.5 (Me), 52.3 (MeO), 118.7 (C), 124.3 (C), 126.2 (CH), 128.6 (2 CH), 129.4 (2 CH), 130.7 (2 CH), 135.2 (2 CH), 135.8 (C), 136.2 (C), 136.8 (C), 143.8 (CH), 144.0 (C), 160.6 (C=O), 162.3 (C=N), 174.6 (C=O). Anal. Calcd. for C₂₁H₁₆BrNO₃S (442.32): C 57.02, H 3.65, N 3.17; found: C 57.15, H 3.74, υ 3.26%.

Ethyl 2-(4-nitrobenzoilimino)-6-(4-methoxyphenyl)-2H-thiopyran- 3-carboxylate (5e): Yellow oil, yield: 0.53 g (60%). IR (KBr, cm^-1): υ 1733, 1716, 1696, 1675, 1578, 1465, 1385, 1263. ¹H NMR (500.1 Hz, CDCl₃): δ 1.27 (t, 3 H, ³J_HH = 7.4, Me), 3.86 (s, 3 H, MeO), 4.26 (q, 2 H, ³J = 7.4, CH₂O), 6.18 (d, 1 H, ³J = 7.5, CH), 7.14 (d, 2 H, ³J = 7.6, 2 CH), 7.38 (d, 1H, ³J = 7.5, CH), 7.56 (d, 2 H, ³J = 7.6, 2 CH), 7.63 (d, 2 H, ³J = 7.6, 2 CH), 8.34 (2 H, d, ³J = 7.8, 2 CH). ¹³C NMR (125.7 Hz, CDCl₃): δ 14.2 (Me), 55.6 (MeO), 61.4 (CH₂O), 114.2 (2 CH), 117.8 (C), 124.8 (2 CH), 127.5 (2 CH), 128.6 (CH), 129.6 (C), 130.2 (2 CH), 138.6 (C), 143.2 (CH), 143.8 (C), 152.4 (C), 161.4 (C=O), 161.8 (C), 162.4 (C=N), 176.8 (C=O). Anal. Calcd. for C₂₂H₁₈N₂O₆S (438.45): C 60.27, H 4.14, N, 6.39; found: C 60.34, H 4.22, N 6.45%.

3. Results and discussion

The reaction of alkyl propiolate 1, benzoyl isothiocyanate 2 and alkyl bromide 3 in the presence of triphenylphosphine 4 under solvent-free conditions produced substituted thiopyran derivatives 5 in good yield (Scheme 1).

The starting point for our experiments was to optimize the reaction conditions such as solvent and reaction time for the production of 2H-thiopyranes which have anti-bacterial ^[4], antihyperplasia ^[5], anti-psychiatric ^[6], and anticancer activities ^[7] (see Table 1).

Table 1
Optimization of reaction conditions of compound 5a.

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Scheme 2.Proposed mechanism for the synthesis of compound 5.

To achieve suitable conditions for the above transformation, a series of experiments was carried out. First, we investigated the reaction of methyl propiolate, benzoyl isothiocyanate, and phenacyl bromide in the presence of triphenyl phosphine in various solvents, in water and under solvent-free classical heating conditions. The reaction proceeds in organic solvents and water with low yield (Table 1, entries 1-10). In the absence of solvent and at 70 ℃, the reaction was performed with good yield after 8 h. Structures of compounds 5a-e were determined based on their IR, ¹H NMR, ¹³C NMR and ³¹P NMR spectra. The mass spectra of these compounds show molecular ion peaks at the appropriate m/z values. In the ¹H NMR spectrum of 5a displayed one singlet at 3.78 for methoxy protons, two doublets at 6.37 (d, ³J = 7.8, CH) and 7.28 (d, ³J = 7.8, CH) for methine protons along with signals for an aromatic moiety. The carbonyl group’s resonances in the ¹³C NMR spectra of 5a appeared at 160.4 (C=O) and 172.4 (C=O) ppm. Also the mass spectra of 5a displayed the molecular ion peak at the appropriate m/z values.

A proposed mechanism for this reaction is shown in Scheme 2. On the basis of phosphorus nucleophile chemistry, it is reasonable to presume that triphenylphosphonium bromide 6 results from initial addition of the triphenylphosphin 4 to α-haloketones 3. Intermediate 6 is reacted with alkyl propiolate 1 in the presence of triethylamine as the base for production of zwitterionic species 7. Then, nucleophilic attack of this intermediate on benzoyl isothiocyanate 2 produces intermediate 8. Finally, by intramolecular cyclization, compound 9 is afforded by elimination of triphenylphosphine oxide, which is converted to 5 as the product.

4. Conclusion

In conclusion, we found that the reaction of alkyl propiolate with benzoyl isothiocyanate and alkyl bromide in the presence of triphenylphosphine leads to a facile synthesis of some functionalized thiopyrans under solvent-free conditions, without using any catalyst.

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