A Synthesis of Functionalized Thiazoles and Pyrimidine-4(3H)-thiones from 1,1,3,3-Tetramethylguanidine, Acetylenic Esters, and Aryl Isothiocyanates

Abstract

Aryl isothiocyanates react with dialkyl 2-{[bis(dimethylamino)methylene]amino}maleates, generated from 1,1,3,3-tetramethylguanidine and acetylenic esters, to afford 2-(dimethylamino)-1,3-thiazole derivatives, functionalized 2-(dimethylamino)-6-thioxo-1,6-dihydropyrimidines, and ethyl 2-(dimethylamino)-6-[(4-nitrophenyl)im­ino]-4-phenyl-6H-1,3-thiazine-5-carboxylate, in moderate to good yields.

Key words

thiazolamines - alkynoate esters - pyrimidinethiones - tetramethylguanidine - aryl isothiocyanates

• References and Notes

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• 10 Compounds 5, 6 and 14: General Procedure TMG (1; 0.115 g, 1 mmol) and the appropriate acetylenic ester 2 (1 mmol) were dissolved in MeCN (5 mL), and the solution was stirred for 1 h at r.t. Aryl isothiocyanate 3 (1 mmol) was added, and the mixture was stirred at the reflux until the reaction was complete [~48 h; TLC (EtOAc–hexane, 1:4)]. The mixture was then filtered and the precipitate was purified by flash column chromatography [silica gel, EtOAc–hexane (1:4)].
• 11 Ethyl 2-(Dimethylamino)-4-phenylthiazole-5-carboxylate (5e) Yellow crystals; yield: 0.17 g (61%); mp 111–113 °C, (Lit.¹² 115–116 °C). IR (KBr): 3382, 2975, 1697, 1566 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 3.15 (s, 6 H), 4.20 (q, J = 7.1 Hz, 2 H), 7.37–7.39 (m, 3 H), 7.76 (d, J = 7.7 Hz, 2 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 14.2 (Me), 40.2 (Me₂N), 60.6 (CH₂O), 110.4 (C), 114.2 (C), 127.6 (2 CH), 128.9 (CH), 129.9 (2 CH), 134.6 (C), 161.9 (C=O), 170.7 (C). EI-MS: m/z (%) = 276/09 (M⁺, 100), 231 (47), 175 (50), 133 (47), 89 (65), 44 (19). Anal. Calcd for C₁₄H₁₆N₂O₂S (276.35): C, 60.85; H, 5.84; N, 10.14. Found: C, 61.13; H, 5.88; N, 10.17. Ethyl 2-(Dimethylamino)-1-(4-methoxyphenyl)-4-phenyl-6-thioxo-1,6-dihydropyrimidine-5-carboxylate (6c) Yellow solid; yield: 0.14 g (34%); mp 116–118 °C. IR (KBr): 3438, 2929, 1685, 1617 cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.25 (t, J = 7.1 Hz, 3 H), 2.85 (s, 6 H), 3.94 (s, 3 H), 4.33 (q, J = 7.1 Hz, 2 H), 7.09 (d, J = 7.9 Hz, 2 H), 7.36 (d, J = 7.9 Hz, 2 H), 7.47–7.56 (m, 3 H), 8.89 (d, J = 6.7 Hz, 2 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.9 (Me), 41.6 (Me₂N), 55.6 (MeO), 61.8 (CH₂O), 114.4 (2 CH), 124.7 (C), 128.4 (2 CH), 128.5 (2 CH), 130.4 (CH), 130.7 (2 CH), 132.9 (C), 137.4 (C), 154.6 (C), 157.5 (C), 159.6 (C), 167.4 (C=O), 185.7 (C=S). EI-MS: m/z (%) = 409.15 (M⁺, 100), 365 (15), 258 (22), 229 (30), 147 (28), 77 (23). Anal. Calcd for C₂₂H₂₃N₃O₃S (409.50): C, 64.53; H, 5.66; N, 10.26. Found: C, 64.84; H, 5.69; N, 10.29. Ethyl (6Z)-2-(Dimethylamino)-6-[(4-nitrophenyl)imino]-4-phenyl-6H-1,3-thiazine-5-carboxylate (14) Yellow solid; yield: 0.31 g (73%); mp 196–198 °C. IR (KBr): 3440 and 2930 (Me), 1721 (CO₂), 1579 (C=N) cm^–1. ¹H NMR (500 MHz, CDCl₃): δ = 1.07 (t, J = 7.1 Hz, 3 H), 3.25 (s, 6 H), 4.17 (q, J = 6.9 Hz, 2 H), 7.12 (d, J = 8.9 Hz, 2 H), 7.49–7.50 (m, 3 H), 7.75 (d, J = 7.4 Hz, 2 H), 8.32 (d, J = 8.9 Hz, 2 H). ¹³C NMR (125.7 MHz, CDCl₃): δ = 13.8 (Me), 38.8 (Me₂N), 61.6 (CH₂O), 108.5 (C), 121.1 (2 CH), 125.6 (2 CH), 128.2 (2 CH), 128.3 (2 CH), 129.7 (CH), 140.2 (C), 144.3 (C), 153.1 (C), 156.1 (C), 158.3 (C), 158.9 (C), 168.1 (C=O). EI-MS: m/z (%) = 424.12 (M⁺, 100), 380 (14), 322 (34), 258 (21), 229 (31), 77 (23). Anal. Calcd for C₂₁H₂₀N₄O₄S (424.48): C, 59.42; H, 4.75; N, 13.20. Found: C, 59.73; H, 4.78; N, 13.23.
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• 13 X-ray diffraction measurements were carried out on a STOE IPDS 2T diffractometer with graphite-monochromated Mo-K_α radiation. All single crystals were obtained from CH₂Cl₂–hexane solutions and mounted on glass fibers. Cell constants and orientation matrices for data collection were obtained by least-square refinement of the diffraction data from 5045, 3838, and 3762 reflections for compounds 5e, 6c, and 14, respectively. Diffraction data were collected in a series of ω scans in 1° oscillations, and integrated by using the STOE X-AREA software package (see Ref. 15). Multiscan absorption corrections were applied by using WinGX-2013.3 software. The structures were solved by direct methods and subsequent difference Fourier maps, and then refined on F² by a full-matrix least-squares procedure using anisotropic displacement parameters. Atomic factors are from the International Tables for X-ray Crystallography. All non-hydrogen atoms were refined with anisotropic displacement parameters. Hydrogen atoms were placed in ideal positions and refined as riding atoms with relative isotropic displacement parameters. All refinements were performed by using the X-STEP32, SHELXL-2014, and WinGX-2013.3 programs (see ref. 16).
• 14 CCDC 1546425, 1530696, and 1530695 contain the supplementary crystallographic data for compounds 5e, 6c, and 14, respectively. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre (CCDC) via www.ccdc.cam.ac.uk/data_request/cif.
• 15 X-AREA: Program for the Acquisition and Analysis of Data, Version 1.30. STOE & Cie GmbH; Darmstadt: 2005

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