Mendeleev Communications Electronic Version, Issue 6, 1999 (pp. 213–255) Reactions of resorcinol with substituted 3,4-dihydro-2(1H)-pyrimidinethiones Sergei I. Filimonov Department of Organic Chemistry, Yaroslavl State Technical University, 150023 Yaroslavl, Russian Federation. Fax: +7 0852 44 0729; e-mail: z55@yaroslavl.ru Acid-catalysed alkylation of resorcinol by substituted tetrahydropyrimidinethiones has been examined.The interaction between pyrimidinethiones and phenolic compounds was first examined by Zigeuner et al.1–2 It was found that pyrimidinethiones formed a product of addition at the 6-position of the pyrimidine ring upon boiling with a tenfold excess of 2,6-dimethylphenol in methanol with concentrated hydrochloric acid as a catalyst. Moreover, Zigeuner et al.1 noted that, when the reaction was performed with 2,4-xylenol under the same conditions, the main reaction product was 2,2-bis(4-hydroxy-3,5-dimethylphenyl)propane. In this study, the reaction of resorcinol addition to pyrimidinethiones 1 has been examined.It is well known3 that rearrangement products, corresponding 1,3-thiazines and aminodihydro- 2(1H)-pyridinethiones, can be formed when the reaction is performed under the above conditions1 (heating with a strong mineral acid).Thermal reactions (zinc chloride catalyst, temperature up to 140 °C) were unsuccessful (the yields were low). Thus, the reaction conditions were changed. The interaction of compounds 1 with resorcinol was examined at temperatures from 40 °C to the boiling temperatures of nonpolar solvents (chloroform, trichloroethylene and toluene) using sulfonic acids as catalysts. The products were separated as a precipitate or oil in 45–90% yields.† It is likely that the reaction is reversible, and complete alkylation can be performed not always even with a large excess of resorcinol.As a rule, a precipitate (oil) separated from the reaction mixture contained up to 80% of the target product, 10–20% of resorcinol and 5–15% of the starting pyrimidinethione (according to HPLC data).† IR spectra were measured on a Bruker IFS-88 spectrometer in the range 700–4000 cm–1 using suspensions of substances in Vaseline oil. 1H NMR spectra of test compounds were recorded on a Bruker AM-300 spectrometer at 300 MHz using 3–5% solutions in [2H6]DMSO.The chemical shifts of protons were measured with reference to an internal standard of HMDS (0.055 ppm). Mass spectra were measured on a MX-1321 mass spectrometer with direct sample injection at 100–150 °C with an ionisation energy of 70 eV. Reversed-phase high-performance liquid chromatography was performed on a Perkin-Elmer instrument (mobile phase: acetonitrile–water, 70:30; stationary phase: C-18).Starting compounds 1 were synthesised according to published procedures. 1,2 The reaction time of the resorcinol alkylation by compounds 1 depends on the structure of the substituent R. The reaction rate depends on the capability of the substituent R to stabilise the intermediate carbocation. Compounds 1 in which R = H exhibited the highest rate of the reaction with resorcinol.The reaction rate dramatically decreased in the order R = H, Me, Ph and C6H4Me-p. In the case of R = C6H4NO2-p, the reaction does almost not proceed under the specified conditions. The effect of the substituent R3 is not so evident; the reaction time was insignificantly shortened in the order Me, Et and Ph, C6H4OMe-p. Compound 2k (R2 = 2-Fur) is an exception, probably, because of its low solubility.The catalyst amount has almost no effect on the reaction time; an amount equal to 10% of the weight of the pyrimidine-thione reactant is sufficient. With higher concentrations, the amount of by-products increases thus decreasing the yield and making the purification difficult. Methanesulfonic acid was tested as a catalyst; however, it did not exhibit considerable advantages.To decide on a solvent, its capability of dissolving the starting pyrimidinethione should be taken into account. For active compounds with R = H, the reaction proceeded with approximately equal ease in toluene, chloroform or trichloroethylene. In contrast, for compounds with R = Ph, the target product was almost not formed in toluene, and the reaction time was halved when the reaction was performed in trichloroethylene. In this case, the reaction temperature exerted a considerable effect. The IR spectra of resorcinol-substituted pyrimidinethiones did not exhibit bands due to double bonds in the pyrimidine ring in the region 1700–1630 cm–1. Not always clearly defined signals (as a rule, as doublets) appear in the regions 3400–3250 and 1000–900 cm–1, which are indicative of the presence of hydroxyl groups in the molecule.The 1H NMR spectra of resorcinol-substituted pyrimidinethiones 2‡ exhibit a spin–spin interaction constant of 13–14 Hz, which is typical of the gem-protons 5-He/5-Ha. Mixtures of rotational isomers (50:50) were detected for compounds with unsymmetrical substituents R (R = m-ClC6H4 and m-CF3C6H4); in this case, the signals of OH, 5-Ha and 6-Me were split into doublets.On this basis, the most downfield signal (split) of a hydroxyl proton can be attributed to the OH group in the a-position with respect to the pyrimidine ring, and the most upfield signal should be attributed to the 6-Me group. N N R3 R S H R1 R2 HO OH HO OH N N R3 R S H R1 R2 H+ D 1a–l 2a–l aR1= R2 = R3 = Me, R = H b R1 = R2 = R3 = R =Me c R1 = R2 = R3 = Me, R = Ph d R1 = R2 = R3 = Me, R = C6H4Me-p e R1 = R2 = R3 = Me, R = C6H4OMe-p f R1 = R2 = R3 = Me, R = C6H4Cl-m g R1 = R2 = R3 = Me, R = C6H4CF3-m h R1 = R = H, R2 = Ph, R3 = Me i R1 = R = H, R2 = R3 = Ph j R1 = R = H, R2 = Ph, R3 = C6H4OMe-p k R1 = R = H, R2 = 2-Fur, R3 = C6H4OMe-p l R1 = R = H, R2 = Ph, R3 = Et aHPLC (retention time).bThe reaction time for syntheses in chloroform. Table 1 Physico-chemical properties of compounds 2. Empirical formula MW mp/°C R.T./ mina Reaction time/hb Yield (%) 2a C13H18N2O2S 266.36 211–213 0.86 1 90 2b C14H20N2O2S 280.4 207–209 0.82 1.5 86 2c C19H22N2O2S 342.46 210–212 0.99 10 74 2d C20H24N2O2S 356.48 225–226 1.07 18 65 2e C20H24N2O3S 372.48 217–218 0.96 6 60 2f C19H21ClN2O2S 376 212–214 0.97 8 72 2g C20H21F3N2O2S 410.45 221–222 1.02 10 76 2h C17H18N2O2S 312.4 210–212 0.90 4 53 2i C22H20N2O2S 376.47 240–242 0.96 3 55 2j C23H22N2O3S 406.50 188–190 0.86 2 71 2k C21H20N2O4S 396.46 193–195 1.00 4 50 2l C18H20N2O2S 328.43 145–147 0.83 1.5 74Mendeleev Communications Electronic Version, Issue 6, 1999 (pp. 213–255) Compounds 2h–2l were isolated as mixtures of the stereoisomers different in the spatial orientation of resorcinol at carbon in the 6-position.The arrangement of the R2 substituent is always equatorial, as evidenced by a large spin–spin interaction constant of 11–12 Hz of vicinal protons 4-Ha/5-Ha equal to 11–12 Hz. The ratio between the isomers depended on the separation procedure; however, isomers with more upfield chemical shifts of hydroxyl proton signals were predominant.‡ General procedure for the synthesis of substituted tetrahydro-6-(2,4- dihydroxyphenyl)-2(1H)-pyrimidinethiones 2. A suspension containing a pyrimidinethione (0.01 mol), resorcinol (0.015 mol) and 0.1 g of toluenesulfonic acid in 20–30 ml of chloroform was boiled for 1–20 h until the formation of a precipitate (oil), which was separated and purified as follows: (i) the precipitate (oil) was dissolved in isopropanol (acetone) on heating; next, the solution was cooled and poured into water with intense stirring; (ii) the oil or solid precipitate was purified by crystallization from acetone–chloroform or acetone–benzene. 2a: 1H NMR, d: 9.11 (s, 1H, OH), 8.78 (s, 1H, OH), 7.83 (s, 1H, NH), 7.68 (s, 1H NH), 6.88 (d, 1H, H12 Rz, J 8.5 Hz), 6.23 (d, 1H, H9 Rz, J 1.8 Hz), 6.16 (dd, 1H, H11 Rz, J 8.5 and 1.8 Hz), 3.0 (d, 1H, 5-He, J 13.3 Hz), 1.53 (d, 1H, 5-Ha, J 13.3 Hz), 1.55 (s, 3H, 4-Mee), 1.19 (s, 3H, 4-Mea), 0.63 (s, 3H, 6-Me).IR, n/cm–1: 3358, 3290, 3180, 1614, 1604, 981, 940. 2b: 1H NMR, d: 9.46 (s, 1H, OH), 9.17 (s, 1H, OH), 9.89 (s 1H, NH), 6.4 (d, 1H, H11 Rz, J 8.0 Hz), 6.32 (s, 1H, H9 Rz), 6.18 (d, 1H, H12 Rz, J 8.0 Hz), 3.3 (s, 3H, NMe), 2.89 (d, 1H, 5-He, J 13.5 Hz), 1.73 (d, 1H, 5-Ha, J 13.5 Hz), 1.68 (s, 3H, 4-Mee), 1.12 (s, 3H, 4-Mea), 0.58 (s, 3H, 6-Me).IR, n/cm–1: 3330, 3200, 1598, 1520, 1500, 975. 2c: 1H NMR, d: 9.28 (s, 1H, OH), 8.98 (s, 1H, OH), 8.09 (s, 1H, NH), 7.7–7.3 (m, 6H, HAr), 6.26 (d, 1H, H9 Rz, J 1.5 Hz), 6.24 (dd, 1H, H11 Rz, J 8.5 and 1.5 Hz), 3.12 (d, 1H, 5-He, J 13.4 Hz), 1.88 (d, 1H, 5-Ha, J 13.4 Hz), 1.40 (s, 3H, 4-Mee), 1.37 (s, 3H, 4-Mea), 0.63 (s, 3H, 6-Me).IR, n/cm–1: 3350, 3320, 975. 2d: 1H NMR, d: 9.55 (s, 1H, OH), 9.35 (s, 1H, OH), 8.2 (s, 1H, NH), 7.2–7.0 (m, 6H, HAr), 6.32 (s, 1H, H9 Rz), 6.23 (d, 1H, H11 Rz, J 8 Hz), 3.12 (d, 1H, 5-He, J 13.8 Hz), 2.37 (s, 3H, MeAr), 2.0 (d, 1H, 5-Ha, J 13.8 Hz), 1.37 (s, 3H, 4-Me), 1.30 (s, 3H, 4-Me), 0.63 (s, 3H, 6-Me).IR, n/cm–1: 3384, 3377, 3190, 1619, 1606, 980, 961. MS, m/z: 356 (50) [M+], 341, 246, 231, 217, 205, 191, 175, 149, 107, 91, 58, 40. 2e: 1H NMR, d: 9.43 (s, 1H, OH), 9.13 (s, 1H, OH), 8.12 (s, 1H, NH), 7.05 (m, 3H, HAr), 6.8 (dd, 2H, HAr, J 9 Hz,) 6.32 (s, 1H, HRz), 6.27 (d, 1H, HRz, J 8.3 Hz), 3.73 (s, 3H, OMe), 2.0 (d, 1H, 5-He, J 13.5 Hz), 1.9 (d, 1H, 5-Ha, J 13.5 Hz), 1.27 (s, 3H, 4-Me), 1.23 (s, 3H, 4-Me), 0.58 (s, 3H, 6-Me).IR, n/cm–1: 3500, 3350, 1619, 1599, 1523, 1500, 1160, 990, 920. 2f: 1H NMR, d: 9.55 (s, 1H, OH), 9.25 (s, 1H, OH), 8.38 (s, 1H, NH), 7.3 (m, 3H, HAr), 7.05 (m, 2H, HAr) 6.32 (m, 2H, HRz), 3.02 (d, 1H, 5-He, J 14.0 Hz) , 1.95 (t, 1H, 5-Ha, J 14.0 Hz), 1.32 (s, 3H, 4-Me), 1.26 (s, 3H, 4-Me), 0.6 (d, 3H, 6-Me).IR, n/cm–1: 3300, 3200, 980, 940. 2g: 1H NMR, d: 9.35 (s, 1H, OH), 9.03 (s, 1H, OH), 8.36 (s, 1H, NH), 7.7–7.3 (m, 4H, HAr), 7.04 (dd, H, H12 Rz, J 8.0 Hz), 6.32 (s, H, H9 Rz), 6.28 (d, H, H12 Rz, J 8.0 Hz), 3.1 (d, 1H, 5-He, J 13.9 Hz), 1.92 (t, 1H, 5-Ha, J 13.9 Hz), 1.3 (s, 6H, 4-Me), 0.6 (s, 3H, 6-Me), a mixture of rotational isomers with OH, Ar and NH doublets.IR, n/cm–1: 3260, 3030, 1605, 1595, 970, 915. MS, m/z: 412 (1.5) [M+], 411 (5.9), 285 (5.6), 261 (6.1), 259 (15.9), 203 (99), 191 (25.9), 182 (22), 175 (100), 161 (20), 150 (23), 145 (22), 135 (14.9). References 1 G. Zigeuner, A. Frank, H. Dujmovits and W. Adam, Monatsh. Chem., 1970, 101, 1415. 2 G. Zigeuner, W. B. Lintschinger and F.Wode, Monatsh. Chem., 1975, 106, 1219. 3 G. Zigeuner, W. B. Lintschinger, A. Fuchsgruber and K. Kollmann, Monatsh. Chem., 1976, 107, 155. Received: 16th April 1999; Com. 99/1477 2i (a mixture of two diastereoisomers in the ratio ~60:40): 1H NMR, d: major isomer, 9.38 (s, 1H, OH), 9.10 (s, 1H, OH), 8.20 (1H, NH), 7.76 (s, 1H, NH), 7.4–7.1 (m, 11H, HAr + HRz), 6.38 (d, 1H, HRz, J 8.0 Hz), 6.32 (s, 1H, HRz), 4.4 (dd, 1H, 4-H, J 11.5 and 2.9 Hz), 3.1 (dd, 1H, 5-H, J 13.5 Hz and 2.9 Hz), 2.1 (dd, 1H, 5-H, J 13.5 and 11.5 Hz); minor isomer, 9.72 (s, 1H, OH), 8.93 (s 1H, OH), 8.28 (s, 1H, NH), 7.53 (s, 1H, NH), 6.22 (d, 1H, HRz), 6.15 (d, 1H, HRz), 3.84 (dd, 1H, 4-H), 2.64 (dd, 1H, 5-H), 2.38 (t, 1H, 5-H). IR, n/cm–1: 3415, 3300, 3200, 1615, 1600, 978. 2h (a mixture of two diastereoisomers in the ratio ~85:15): 1H NMR, d: major isomer, 9.47 (s, 1H, OH), 9.18 (s, 1H, OH), 8.4 (s, 1H, NH), 8.0 (s, 1H, NH), 7.40–7.15 (m, 5H, HAr), 6.9 (d, 1H, H12 Rz, J 8.0 Hz), 6.35 (s, 1H, H9 Rz), 6.23 (d, 1H, H11 Rz, J 8.0 Hz), 3.78 (dd, 1H, 4-H, J 11.5 and 3.0 Hz), 2.98 (dd, 1H, 5-He, J 12.6 and 3.0 Hz), 1.58 (dd, 1H, 5-Ha, J 12.6 and 11.5 Hz), 1.53 (s, 3H, 6-Me); minor isomer, 9.8 (s, 1H, OH), 9.12 (s 1H, OH), 8.23 (s, 1H, NH), 8.12 (s, 1H, NH), 6.22 (d, 1H, HRz), 6.15 (d, 1H, HRz), 4.23 (dd, 1H, 4-H), 2.9 (dd, 1H, 5-H), 1.7 (t, 1H, 5-H).IR, n/cm–1: 3350, 3120, 1615, 1595, 975. 2j (a mixture of two diastereoisomers in the ratio ~60:40): 1H NMR, d: major isomer, 9.7 (s, 1H, OH), 9.08 (s, 1H, OH), 8.28 (s, 1H, NH), 8.15 (s, 1H, NH), 7.4–6.15 (m, 12H, HAr + HRz), 3.88 (dd, 1H, 4-H, J 11.8 and 3.0 Hz), 3.76 (s, 3H, OMe), 2.6 (dd, 1H, 5-H, J 13.2 and 3.0 Hz), 2.35 (dd, 1H, 5-H, J 13.2 and 11.8 Hz); minor isomer, 9.32 (s, 1H, OH), 9.1 (s, 1H, OH), 8.25 (s, 1H, NH), 7.68 (s, 1H, NH), 4.32 (dd, 1H, 4H, J 11.8 and 3.0 Hz), 3.72 (s, 3H, OMe), 3.12 (dd, 1H, 5-H, J 13.2 and 3.0 Hz), 2.1 (dd, 1H, 5-H, J 13.2 and 11.8 Hz).IR, n/cm–1: 3250, 3380, 1603, 1540, 1040, 978. MS, m/z: 406 [M+], 396, 330, 296, 253, 236, 219, 177, 165, 148, 134, 110, 104, 82, 76, 53, 39. 2k (a mixture of two diastereoisomers in the ratio ~95:5): 1H NMR, d: 9.32 (s, 1H, OH), 9.09 (s, 1H, OH), 8.16 (1H, NH), 7.69 (s, 1H, NH), 7.45 (s, 1H, 3-HFu), 7.13 (m, 3H, HAr + HFu), 6.78 (d, 2H, HAr, J 9.5 Hz), 6.3 (m, 4H, HRz + HFu), 4.35 (dd, 1H, 4-H, J 11.1 and 3.0 Hz), 3.72 (s, 3H, OMe), 3.15 (dd, 1H, 5-H, J 13.9 and 3.0 Hz), 2.38 (dd, 1H, 5-H, J 13.9 and 11.1 Hz). IR, n/cm–1: 3440, 3250, 1618, 1598, 1036, 1018, 982, 930. 2l (a mixture of two diastereoisomers in the ratio ~90:10): 1H NMR, d: 9.25 (s, 1H, OH), 8.95 (s, 1H, OH), 7.75 (s, 1H, NH), 7.7 (s, 1H, NH), 7.4–7.15 (m, 5H, HAr), 6.9 (d, 1H, H12 Rz), 6.35 (d, 1H, H9 Rz), 6.23 (dd, 1H, H5 Rz), 3.9 (dd, 1H, 4-H, J 11.6 and 3.0 Hz), 2.9 (dd, 1H, 5-H, J 12.6 and 3.0 Hz), 1.78 (dd, 1H, 5-H, J 11.6 and 12.6 Hz), 2.03 (m, 1H, CH2), 1.87 (m, 1H, CH2), 0.78 (t, 3H, Me).