Introduction

Multicomponent reactions are valuable tools for the preparation of structurally diverse drug-like heterocyclic compounds [1]. MCR designed to produce biologically active compounds has become an important area of research in organic, combinatorial, and medicinal chemistry [2].

Xanthenes (tricyclic dibenzopyrans) are one of the most widely distributed classes of natural compounds and possess diverse pharmacological properties, such as antiviral [3], anti-inflammatory [4], and anti-cancer [5, 6] activity. They are also used as antagonists for paralyzing the action of zoxazolamine [7], in photodynamic therapy (PDT) [8], and as antagonists for drug resistant leukemia lines [9]. 9-(2-Hydroxy-4,4-dimethyl-6-oxo-1-cyclohexen-1-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-ones are well-known as orally active and selective Y5 antagonists [10]. Correlations between the in vitro function and the binding activity of different peptide agonists and their potent stimulation of food intake have found the Y5 receptor as a major feeding receptor [11].

2,4,6-Trioxohexahydropyrimidine or barbituric acid is a type of privileged medicinal scaffold also called barbiturates. Barbiturates are the famous class of drugs that act as central nervous system depressants, and by virtue of this produce a wide spectrum of effects, from mild sedation to anesthesia [12]. They are also effective as anxiolytics and as anticonvulsants [13]. The current interest in barbiturates arises from their pharmacological potential as analeptics, immunomodulating and anti-AIDS agents, and also as anticancer remedies [14].

Thus, the 10-(2,4,6-trioxohexahydropyrimidin-5-yl)-3,3-dimethyl-2,3,4,9-tetrahydro-1H-xanthen-1-one system appears to be of the interest because it incorporates a tetrahydro-1H-xanthen-1-one and a 2,4,6-trioxohexahydropyrimidine heterocyclic ring, which are both promising with respect to biological responses. Recently two catalytic methods were suggested for 10-(2,4,6-trioxohexahydropyrimidin-5-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-one synthesis from salicylaldehydes, dimedone, and barbituric acid under different catalytic conditions. Among these catalysts are known L-prolin (10 mol%) [15] and TH amino acid catalyst [16] (20 % by weight of salicylaldehyde), which was specially obtained by tedious hydrolysis of bovine tendon [16]. In the case of L-prolin as catalyst only one example of this multicomponent reaction is known. From salicylaldehyde, dimedone, and barbituric acid (80 °C, 6 h) 2,4,6-trioxohexahydropyrimidine substituted tetrahydro-1H-xanthen-1-one 1 was obtained in 87 % yield [15]. The similar reaction with TH amino acid catalyst resulted in only 56 % yield of 1 after 24 h heating at 80 °C [16] (Scheme 1).

scheme 1

Both these catalytic methods are characterized by heating at 80 °C during long reaction time (6–24 h), and resulted in moderate yields of tetrahydro-1H-xanthen-1-one 1 [15, 16]. Moreover, from the position of ‘green chemistry’ one could formulate that ‘the best catalyst is no catalyst’ [17, 18]. Thus, the two known procedures for the synthesis of tetrahydro-1H-xanthen-1-ones 1 have its merits, but the fast, simple, and efficient non-catalytic method for this tandem Knoevenagel–Michael process with further cyclization has yet to be developed.

Recently, we have found non-catalytic fast and efficient multicomponent transformation of isatin, cyclic C–H acids, and malononitrile into spirooxoindoles [19], general non-catalytic approach to spiroacenaphthylene heterocycles from acenaphthenequinone, cyclic CH-acids, and malononitrile [20], and also non-catalytic efficient approach to substituted 2,3,4,9-tetrahydro-1H-xanthen-1-ones from salicylaldehydes and dimedone [21].

Considering our results on the non-catalytic multicomponent and cascade transformation of C–H acids and salicylaldehydes [19–21] as well as the certain biomedical application of 10-(2,4,6-trioxo-hexahydropyrimidin-5-yl)-2,3,4,9-tetrahydro-1H-xanthen-1-ones mentioned above, we were prompted to design a convenient fast and facile non-catalytic methodology for the efficient synthesis of substituted tetrahydro-1H-xanthen-1-ones based on multicomponent reaction of salicylaldehydes, dimedone, and barbituric acids.

Results and discussion

As it follows from introduction, we were interested in designing a fast, convenient, and facile non-catalytic methodology for the efficient synthesis of functionalized tetrahydro-1H-xanthen-1-one system based on multicomponent reaction of salicylaldehydes 2a–2g, dimedone, and barbituric acids 3a–3c (Scheme 2; Tables 1, 2).

scheme 2
Table 1 Multicomponent transformation of salicylaldehyde (2a), dimedone, and N,N′-dimethylbarbituric acid (3a) into tetrahydro-1H-xanthen-1-one 4a
Full size table
Table 2 Non-catalytic multicomponent transformation of salicylaldehydes 2a–2f, dimedone, and barbituric acids 3a–3c into substituted tetrahydro-1H-xanthen-1-ones 4a–4h
Full size table

On the first step of this investigation the transformation of salicylaldehyde (2a), dimedone, and N′,N′-dimethylbarbituric acid (2a) into tetrahydro-1H-xanthen-1-one 4a was studied (Table 1). In ethanol as a solvent under reflux (78 °C) in the presence of NaOAc or KF as catalyst in only 5 min reaction time tetrahydro-1H-xanthen-1-one 4a was obtained in 85–92 % yield (Table 1, entries 1–4). The more interesting was the fact that just the same result (93 % yield) was achieved in ethanol without any catalyst (Table 1, entry 5). Somewhat lower yields of 75–91 % were found when multicomponent reaction was carried out in water, methanol, n-propanol, or even under solvent-free conditions without catalyst under heating (Table 1, entries 5–9). The best yield 95 % of tetrahydro-1H-xanthen-1-one 4a was obtained in ethanol with the minimal quantity of solvent (Table 1, entry 10).

Under the optimal conditions thus found, salicylaldehydes 2a–2f, dimedone, and barbituric acids 3a–3c were transformed into corresponding substituted tetrahydro-1H-xanthen-1-ones 4a–4h in 90–95 % yields (Table 2).

With the above results taken into consideration and the mechanistic data on non-catalytic multicomponent processes [19–21], the following mechanism for the non-catalytic multicomponent transformation of salicylaldehydes 2, dimedone, and barbituric acids 3 into substituted tetrahydro-1H-xanthen-1-ones 4 is proposed. The initiation step of the catalytic cycle begins with the thermal deprotonation of a molecule of dimedone, which leads to the dimedone anion A formation (Scheme 3). The following process represents a typical multicomponent reaction. Knoevenagel condensation of the anion A with salicylaldehyde 2 takes place with the elimination of a hydroxide anion and formation of Knoevenagel adduct 5 [22]. The subsequent hydroxide-promoted Michael addition of barbituric acids 3 to electron-deficient Knoevenagel adduct 5 results in anions B and C formation. Protonation of anion C with the next molecule of dimedone leads to the corresponding tetrahydro-1H-xanthen-1-one 4 formation with the regeneration of anion A at the last step of the catalytic cycle (Scheme 3).

scheme 3

Thus, the simple non-catalytic procedure can produce a fast (5 min), efficient, and selective multicomponent transformation of salicylaldehydes, dimedone, and barbituric acids into substituted tetrahydro-1H-xanthen-1-ones in excellent 90–95 % yields. This new process opens an efficient and convenient multicomponent way to create substituted tetrahydro-1H-xanthen-1-ones, the pharmacologically active substances with known antiviral, anti-inflammatory, anti-cancer activity and promising compounds for different biomedical applications. This non-catalytic multicomponent procedure utilizes simple equipment; it is easily carried out and is valuable from the viewpoint of environmentally benign diversity-oriented large-scale processes.

Experimental

All melting points were measured with a Gallenkamp melting-point apparatus. 1H and 13C NMR spectra were recorded in CDCl3 with a Bruker Avance II 300 spectrometer at ambient temperature. Chemical shift values are relative to Me4Si. IR spectra were recorded with a Bruker ALPHA-T FT-IR spectrometer in KBr pellets. Mass-spectra (EI, 70 eV) were obtained directly with a Kratos MS-30 spectrometer. High-resolution mass spectrometry (HRMS) (electrospray ionization, ESI) was measured on a Bruker microTOF II instrument; external or internal calibration was done with an electrospray calibrant solution (Fluka). All chemicals used in this study were commercially available.

General procedure

A solution of salicylaldehyde (5 mmol), barbituric acid (5 mmol), and 0.7 g dimedone (5 mmol) in 1 cm3 ethanol was stirred under reflux for 5 min. Then the precipitated product was filtered off, rinsed with 2 cm3 ice-cold ethanol–water solution (1:1), and dried under reduced pressure.

5-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethyl-pyrimidine-2,4,6(1H,3H,5H)-trione (4a, C21H22N2O5)

Yield 95 %; m.p.: 212–213 °C; 1H NMR (300 MHz, CDCl3): δ = 1.13 (s, 3H, CH3), 1.19 (s, 3H, CH3), 2.24 (s, 2H, CH2), 2.47 (d, J = 17.7 Hz, 1H, CH2), 2.57 (d, J = 17.7 Hz, 1H, CH2), 3.07 (s, 3H, N–CH3), 3.22 (s, 3H, N–CH3), 3.86 (d, J = 2.7 Hz, 1H, CH), 4.87 (d, J = 2.7 Hz, 1H, CH), 7.03 (d, J = 8.1 Hz, 1H, Ar), 7.07–7.12 (m, 2H, Ar), 7.19–7.29 (m, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3): δ = 27.3, 28.3, 28.4, 29.4, 32.1, 36.4, 41.6, 50.7, 55.1, 109.0, 116.8, 120.6, 125.1, 128.0, 129.1, 150.5, 151.3, 167.1, 167.3, 168.1, 197.3 ppm; IR (KBr): \(\bar{v}\) = 3428, 3412, 2962, 2951, 1690, 1676, 1643, 1391, 1376, 1229 cm−1; MS (EI, 70 eV): m/z (%) = 382 ([M]+, 6), 298 (5), 227 (100), 171 (96), 143 (19), 115 (84), 69 (30), 58 (32), 42 (56), 28 (61); HRMS (ESI): m/z calcd for C21H24N2NaO5 [M+Na]+ 405.1421, found 405.1412.

1,3-Dimethyl-5-(3,3,7-trimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-pyrimidine-2,4,6(1H,3H,5H)-trione (4b, C22H24N2O5)

Yield 91 %; m.p.: 179–180 °C; 1H NMR (300 MHz, CDCl3): δ = 1.12 (s, 3H, CH3), 1.18 (s, 3H, CH3), 2.28 (s, 3H, CH3), 2.33 (s, 2H, CH2), 2.45 (d, J = 17.7 Hz, 1H, CH2), 2.55 (d, J = 17.7 Hz, 1H, CH2), 3.08 (s, 3H, N–CH3), 3.22 (s, 3H, N–CH3), 3.84 (d, J = 2.7 Hz, 1H, CH), 4.81 (d, J = 2.7 Hz, 1H, CH), 6.91 (d, J = 8.3 Hz, 2H, Ar), 7.04 (dd, J 1  = 8.3 Hz, J 2  = 2.0 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3): δ = 20.8, 27.4, 28.3 (2C), 29.4, 32.1, 36.8, 41.7, 50.7, 55.1, 108.7, 116.4, 120.2, 128.3, 129.8, 134.9, 148.5, 151.4, 167.2, 167.5, 168.3, 197.3 ppm; IR (KBr): \(\bar{v}\) = 2959, 2877, 2888, 1695, 1678, 1631, 1458, 1388, 1229, 1111 cm−1; MS (EI, 70 eV): m/z (%) = 396 ([M]+, 1), 241 (100), 225 (7), 185 (35), 157 (14), 128 (29), 115 (14), 69 (24), 58 (36), 42 (55); HRMS (ESI): m/z calcd for C22H24N2NaO5 [M+Na]+ 419.1577, found 419.1564.

5-(5-Ethoxy-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4c, C23H26N2O6)

Yield 96 %; m.p.: 164–165 °C; 1H NMR (300 MHz, CDCl3): δ = 1.13 (s, 3H, CH3), 1.19 (s, 3H, CH3), 1.45 (t, J = 7.0 Hz, 3H, CH3), 2.34 (s, 2H, CH2), 2.54 (d, J = 17.7 Hz, 1H, CH2), 2.65 (d, J = 17.7 Hz, 1H, CH2), 3.08 (s, 3H, N–CH3), 3.21 (s, 3H, N–CH3), 3.86 (d, J = 2.6 Hz, 1H, CH), 3.96–4.19 (m, 2H, CH2), 4.86 (d, J = 2.6 Hz, 1H, CH), 6.64 (d, J = 7.7 Hz, 1H, Ar), 6.82 (d, J = 7.7 Hz, 1H), 7.00 (t, J = 8.0 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ = 14.8, 27.4, 28.3, 28.4, 29.4, 32.2, 36.7, 41.6, 50.8, 55.0, 64.8, 108.8, 112.9, 119.3, 121.6, 124.8, 140.6, 147.3, 151.4, 167.1, 167.3, 168.1, 197.5 ppm; IR (KBr): \(\bar{v}\) = 2957, 1676, 1648, 1469, 1421, 1388, 1287, 1225, 1194, 1075 cm−1; MS (EI, 70 eV): m/z (%) = 426 ([M]+, 8), 410 (4), 326 (8), 271 (100), 255 (9), 215 (11), 187 (12), 159 (5), 115 (8), 69 (8); HRMS (ESI): m/z calcd for C23H26N2NaO6 [M+Na]+ 449.1683, found 449.1665.

5-(7-Bromo-5-methoxy-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4d, C22H23BrN2O6)

Yield 92 %; m.p.: 188–189 °C; 1H NMR (300 MHz, CDCl3): δ = 1.12 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.29 (d, J = 16.3 Hz, 1H, CH2), 2.35 (d, J = 16.3 Hz, 1H, CH2), 2.52 (d, J = 17.7 Hz, 1H, CH2), 2.61 (d, J = 17.7 Hz, 1H, CH2), 3.16 (s, 3H, N–CH3), 3.24 (s, 3H, N–CH3), 3.87 (s, 3H, CH3), 3.83 (d, J = 2.6 Hz, 1H, CH), 4.82 (d, J = 2.6 Hz, 1H, CH), 6.89 (d, J = 1.8 Hz, 1H, Ar), 6.94 (d, J = 1.8 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3): δ = 27.3, 28.4, 28.5, 29.3, 32.2, 35.8, 41.5, 50.7, 55.1, 56.4, 108.6, 114.8, 117.2, 122.2, 123.6, 139.5, 148.6, 151.3, 166.9, 167.1, 167.7, 197.4 ppm; IR (KBr): \(\bar{v}\) = 2964, 2955, 1676, 1646, 1575, 1483, 1422, 1382, 1225, 1191 cm−1; MS (EI, 70 eV): m/z (%) = 492 ([M]+, 2), 490 ([M]+, 3), 337 (5), 335 (6), 279 (2), 172 (4), 156 (3), 115 (7), 69 (18), 28 (100); HRMS (ESI): m/z calcd for C22H23BrN2NaO6 [M+Na]+ 513.0632, found 513.0622.

5-(7-Chloro-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4e, C21H21ClN2O5)

Yield 90 %; m.p.: 207–208 °C; 1H NMR (300 MHz, CDCl3): δ = 1.13 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.29 (d, J = 16.2 Hz, 1H, CH2), 2.35 (d, J = 16.2 Hz, 1H, CH2), 2.47 (d, J = 17.8 Hz, 1H, CH2), 2.54 (d, J = 17.8 Hz, 1H, CH2), 3.16 (s, 3H, N–CH3), 3.24 (s, 3H, N–CH3), 3.85 (d, J = 2.5 Hz, 1H, CH), 4.85 (d, J = 2.5 Hz, 1H, CH), 6.98 (d, J = 8.7 Hz, 1H, Ar), 7.16 (d, J = 2.3 Hz, 1H, Ar), 7.21 (dd, J 1  = 8.7 Hz, J 2  = 2.3 Hz, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3): δ = 27.2, 28.4, 28.5, 29.4, 32.1, 35.6, 41.5, 50.7, 55.2, 108.6, 118.1, 123.0, 128.0, 129.1, 130.2, 149.1, 151.2, 166.9, 167.1, 167.9, 197.4 ppm; IR (KBr): \(\bar{v}\) = 2961, 2883, 1678, 1633, 1684, 1678, 1633, 1456, 1386, 1235 cm−1; MS (EI, 70 eV): m/z (%) = 418 ([M]+, 2), 416 ([M]+, 5), 332 (4), 261 (99), 245 (12), 205 (97), 149 (78), 114 (30), 83 (33), 42 (100); HRMS (ESI): m/z calcd for C21H21ClN2NaO5 [M+Na]+ 439.1031, found 439.1023.

5-(7-Bromo-3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (4f, C21H21BrN2O5)

Yield 93 %; m.p.: 209–210 °C; 1H NMR (300 MHz, CDCl3): δ = 1.13 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.28 (d, J = 16.3 Hz, 1H, CH2), 2.35 (d, J = 16.3 Hz, 1H, CH2), 2.47 (d, J = 18.0 Hz, 1H, CH2), 2.54 (d, J = 18.0 Hz, 1H, CH2), 3.16 (s, 3H, N–CH3), 3.25 (s, 3H, N–CH3), 3.84 (d, J = 2.5 Hz, 1H, CH), 4.84 (d, J = 2.5 Hz, 1H, CH), 6.92 (d, J = 8.6 Hz, 1H, Ar), 7.31 (d, J = 1.9 Hz, 1H, Ar), 7.35 (dd, J 1  = 8.6 Hz, J 2  = 1.9 Hz, 1H) ppm; 13C NMR (75 MHz, CDCl3): δ = 27.2, 28.4, 28.5, 29.4, 32.2, 35.7, 41.6, 50.7, 55.2, 108.7, 117.5, 118.5, 123.4, 131.0, 132.0, 149.6, 151.2, 166.9, 167.1, 167.9, 197.4 ppm; IR (KBr): \(\bar{v}\) = 2960, 2877, 1679, 1634, 1455, 1416, 1386, 1234, 1187, 1111, 1037 cm−1; MS (EI, 70 eV): m/z (%) = 462 ([M]+, 7), 460 ([M]+, 8), 307 (100), 305 (93), 251 (4), 249 (4), 142 (9) 114 (12), 58 (28), 42 (45); HRMS (ESI): m/z calcd for C21H21BrN2NaO5 [M+Na]+ 483.0526, found 483.0516.

1,3-Diethyl-5-(3,3-dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)-pyrimidine-2,4,6(1H,3H,5H)-trione (4g, C23H26N2O5)

Yield 90 %; m.p.: 115–116 °C; 1H NMR (300 MHz, CDCl3): δ = 0.90 (t, J = 7.0 Hz, 3H, CH3), 1.13 (s, 3H, CH3), 1.21 (t, J = 7.0 Hz, 3H, CH3), 1.22 (s, 3H, CH3), 2.35 (s, 2H, CH2), 2.47 (d, J = 17.6 Hz, 1H, CH2), 2.59 (d, J = 17.6 Hz, 1H, CH2), 3.56–3.78 (m, 2H, CH2), 3.82–3.94 (m, 2H, CH2), 3.86 (d, J = 2.5 Hz, 1H, CH), 4.91 (d, J = 2.5 Hz, 1H, CH), 7.01 (d, J = 8.3 Hz, 1H, Ar), 7.07 (t, J = 6.3 Hz, 2H, Ar), 7.19–7.29 (m, 1H, Ar) ppm; 13C NMR (75 MHz, CDCl3): δ = 12.7, 13.1, 27.6, 29.2, 32.3, 36.4, 36.9, 37.3, 41.7, 50.8, 54.4, 109.3, 117.0, 120.4, 125.0, 128.2, 129.1, 150.5, 150.6, 166.7, 167.2, 168.0, 197.3 ppm; IR (KBr): \(\bar{v}\) = 2980, 2953, 1677, 1652, 1458, 1406, 1387, 1310, 1231, 1125 cm−1; MS (EI, 70 eV): m/z (%) = 410 ([M]+, 5), 326 (2), 267 (4), 227 (100), 211 (8), 171 (35), 115 (28), 69 (14), 44 (14), 29 (34); HRMS (ESI): m/z calcd for C23H26N2NaO5 [M+Na]+ 433.1734, found 433.1724.

5-(3,3-Dimethyl-1-oxo-2,3,4,9-tetrahydro-1H-xanthen-9-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (4h)

Yield 92 %; m.p.: 166–167 °C (Ref. [15] m.p.: 150–152 °C); 1H NMR (300 MHz, CDCl3): δ = 1.13 (s, 3H, CH3), 1.15 (s, 3H, CH3), 2.35 (s, 2H, CH2), 2.48 (d, J = 17.6 Hz, 1H, CH2), 2.56 (d, J = 17.6 Hz, 1H, CH2), 3.88 (d, J = 2.3 Hz, 1H, CH), 4.94 (d, J = 2.3 Hz, 1H, CH), 7.02 (d, J = 8.0 Hz, 1H, Ar), 7.10 (t, J = 7.2 Hz, 1H, Ar), 7.23 (d, J = 7.2 Hz, 1H, Ar), 8.76 (s, 1H, NH), 8.94 (s, 1H, NH) ppm.