Naphtho- and benzopyranopyrimidines are important heterocycles in pharmaceutical chemistry. They include compounds having antibacterial and fungicidal activity [1] as well as behaving as antagonists of the neuropeptide S receptor [2] and showing antiallergic properties [3].

In general, 1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2,4(3H)-diones unsubstituted at position 5 or containing an aryl substituent are prepared by reduction of 2H-chromeno[2,3-d]pyrimidine-2,4(3H)-diones [37] or the corresponding pyrilium salts [8], through the cyclization of certain barbituric acid derivatives [3], or by high- temperature condensation of salicyl alcohol with 6-chlorouracil [7,9]. In addition, the electron-rich 3,4-methylene-dioxyphenol can be used in a three-component condensation with barbituric acid and aromatic aldehydes [1013]. At the same time, existing methods of synthesis generally preclude the preparation of 1,5-dihydro-2H-chromeno[2,3-d]-pyrimidine-2,4(3H)-diones substituted at a nitrogen atom or are limited to single examples.

We have proposed a novel method for the synthesis of 1,5-dihydro-2H-chromeno[2,3-d]pyrimidine-2,4(3H)-diones 3a-f from 6-amino-1,3-dimethyluracil (1) and the o-benzoquinone methide precursors, namely, o-hydroxybenzyl alcohols 2a-d, Mannich base 2e, and quaternary ammonium salt 2f. The reactions were carried out by refluxing an equimolar mixture of the reagents for 5-10 h in acetic acid. A single recrystallization gave chromatographically pure materials in 38-85% yields. The low yield of chromenopyrimidine 3f is apparently due to the ready oligomerization of the corresponding sterically unshielded o-quinone methide.

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A possible reaction mechanism involves an initial thermal decomposition of the o-hydroxybenzyl derivatives 2 to form the corresponding o-quinone methide heterodienes A [14,15], which then react with 6-amino-1,3-dimethyluracil (1) (behaving as a dienophile) to give the cycloadduct B. Subsequent elimination of ammonia leads to the chromenopyrimidines 3.

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The IR spectra of compounds 3a-f show characteristic absorption bands in the ranges 1701-1711 and 1657-1678 cm-1 corresponding to the carbonyl groups. Absorption bands for hydroxyl and amino groups are absent in the IR spectra which confirms the cyclic structure of compounds 3a-f. According to the 1H NMR data, the methyl group protons at positions 1 and 3 appear as two three-proton singlets at 3.25-3.38 and 3.48-3.66 ppm. In the 13C NMR spectra, the methyl group carbon atoms resonate at 28.2-28.4 and 29.0-30.6 ppm and the C-4a atom at 85.4-94.4 ppm. In the DEPT spectra the number of protons directly bonded with the 13C atoms agrees with the proposed structures.

The main advantage of the developed method for preparing the 2H-chromeno[2,3-d]pyrimidinediones is the potential use of substituted o-benzoquinone methide precursors which contain donor or sterically bulky substituents in the benzene ring and also the preparation of derivatives which are unsubstituted at position 5 or contain an alkyl or aryl group.

IR spectra were recorded on a Shimadzu IRAffinity-1 spectrometer for KBr pellets. 1H and 13C NMR spectra (400 and 100 MHz, respectively) and the DEPT spectra were recorded on a JEOL JNM-ECX400 spectrometer using CDCl3 with TMS as internal standard. Mass spectra were recorded on a Finnigan Trace DSQ instrument (EI ionization, 70 eV). Elemental analysis was performed on a Euro Vector EA-3000 automatic CHNS analyzer. Melting points were determined by the capillary method on a PTP-M apparatus. Thin-layer chromatography was carried out on Silufol UV-254 plates and revealed using UV light or iodine vapor. The o-quinone methide precursors were prepared by known methods [1618].

Preparation of the 1,5-Dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-diones 3a-f (General Method). A mixture of the 6-amino-1,3-dimethyluracil (1) (0.54 g, 3.5 mmol) and the o-benzoquinone methide precursor (2a-f) (3.5 mmol) in AcOH (10 ml) (in the case of compound 3a – 30 ml) was refluxed for 5 h (10 h for compound 3a). Solvent was evaporated in vacuo and the residue was purified by recrystallization.

9-(1-Adamantyl)-1,3,7-trimethyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3a). Yield 77%. Colorless crystals. Mp 266-267°С (EtOH–DMF, 9:1). IR spectrum, ν, cm-1: 2905, 2886, 2847, 1711, 1674, 1645, 1491, 1447, 1341, 1215, 1190, 860, 760. 1H NMR spectrum, δ, ppm (J, Hz): 1.74-1.82 (6H, m, 3СH2 Ad); 2.10 (9H, br. s, 3CH Ad, 3CH2 Ad); 2.29 (3H, s, 7-CH3); 3.38 (3H, s, NCH3); 3.66 (3H, s, NCH3); 3.69 (2H, s, 5-CH2); 6.87 (1H, d, J = 1.6) and 6.96 (1H, d, J = 1.6, H-6,8). 13C NMR spectrum, δ, ppm: 21.0 (7-CH3); 22.3 (5-CH2); 28.2 (NCH3); 28.9 (3CH Ad); 30.6 (NCH3); 36.9 (3CH2 Ad, C Ad); 40.8 (3CH2 Ad); 85.4 (C-4a); 120.0 (C); 126.8 (CH); 128.1 (CH); 134.8 (C); 137.7 (C); 146.5 (C); 151.0 (C); 152.7 (C); 162.8 (C). Mass spectrum, m/z (I rel, %): 392 [M]+ (100), 391 (54), 379 [M-CH3]+ (13), 335 (29). Found, %: С 73.52; Н 7.15; N 7.09. C24H28N2O3. Calculated, %: С 73.44; Н 7.19; N 7.14.

5-Isopropyl-1,3-dimethyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3b). Yield 54%. Colorless crystals. Mp 119-121°С (EtOH–H2O, 9:1). IR spectrum, ν, cm-1: 2959, 1709, 1659, 1641, 1580, 1497, 1481, 1456, 1368, 1236, 1192, 1111, 758. 1H NMR spectrum, δ, ppm (J, Hz): 0.59 (3H, d, J = 6.9) and 0.92 (3H, d, J = 6.9, CH(CH 3)2); 2.00-2.07 (1H, m, CH2); 3.35 (3H, s, NCH3); 3.50 (3H, s, NCH3); 3.92 (1H, d, J = 2.5, 5-СН); 7.08 (1H, d, J = 8.0, Н Ar); 7.13-7.20 (2H, m, Н Ar); 7.24 (1H, t, J = 7.3, Н Ar). 13C NMR spectrum, δ, ppm: 17.4, 20.2 (CH(CH3)2); 28.3 (NCH3); 29.1 (NCH3); 34.3 (CHMe2); 38.9 (5-CH); 90.0 (C-4a); 116.1 (CH); 123.0 (C); 125.2 (CH); 127.8 (CH); 129.9 (CH); 150.9 (2C); 154.1 (C); 162.3 (C). Mass spectrum, m/z (I rel, %): 286 [M]+ (<1), 243 [M-С3Н7]+ (100), 186 (10), 142 (10). Found, %: С 67.05; Н 6.37; N 9.66. C16H18N2O3. Calculated, %: С 67.12; Н 6.34; N 9.78.

1,3-Dimethyl-5-phenyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3c). Yield 81%. Colorless crystals. Mp 227–229°С (AcOH). IR spectrum, ν, cm-1: 1705, 1665, 1647, 1584, 1487, 1445, 1439, 1267, 1240, 1180, 1113, 1051, 974, 768, 758, 750, 708, 542. 1H NMR spectrum, δ, ppm (J, Hz): 3.29 (3H, s, NCH3); 3.58 (3H, s, NCH3); 5.16 (1H, s, 5-СН); 7.09-7.19 (4H, m, Н Ar); 7.22-7.27 (5H, m, Н Ar). 13C NMR spectrum, δ, ppm: 28.2 (NCH3); 29.2 (NCH3); 39.0 (5-CH); 90.6 (C-4a); 116.6 (CH); 124.7 (C); 126.2 (CH); 127.0 (CH); 128.0 (2CH); 128.2 (CH); 128.7 (2CH); 130.3 (CH); 145.2 (C); 148.9 (C); 150.9 (C); 152.8 (C); 162.0 (C). Mass spectrum, m/z (I rel, %): 320 [M]+ (68), 243 (100), 242 (73), 186 (30). Found, %: С 71.17; Н 4.94; N 8.67. C19H16N2O3. Calculated, %: С 71.24; Н 5.03; N 8.74.

1,3-Dimethyl-5,5-diphenyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3d). Yield 85%. Colorless crystals. Mp 230-231°С (EtOH). IR spectrum, ν, cm-1: 3059, 3032, 1703, 1657, 1576, 1479, 1447, 1435, 1396, 1288, 1256, 1227, 1173, 770, 754, 727, 702. 1H NMR spectrum, δ, ppm (J, Hz): 3.25 (3H, s, NCH3); 3.58 (3H, s, NCH3); 6.84 (1H, dd, J = 8.0, J = 1.4, H Ar); 7.06 (1H, td, J = 8.2, J = 1.4, H Ar); 7.18-7.30 (12H, m, H Ar). 13C NMR spectrum, δ, ppm: 28.4 (NCH3); 29.4 (NCH3); 51.0 (C-5); 94.4 (C-4a); 115.9 (CH); 125.7 (CH); 126.6 (2CH Ph); 127.9 (4CH Ph); 128.2 (CH); 128.8 (C); 129.1 (4CH Ph); 131.6 (CH); 145.8 (2C Ph); 148.2 (C); 150.7 (C); 153.5 (C); 161.1 (C). Mass spectrum, m/z (I rel, %): 396 [M]+ (12), 319 [M-C6H5]+ (100), 262 (23). Found, %: С 75.74; Н 4.99; N 7.17. C25H20N2O3. Calculated, %: С 75.74; Н 5.08; N 7.07.

9-(1-Adamantyl)-7-( tert -butyl)-1,3-dimethyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3e). Yield 69%. Colorless crystals. Mp 220-222°С (EtOH). IR spectrum, ν, cm-1: 2959, 2909, 2851, 1710, 1678, 1651, 1601, 1501, 1462, 1439, 1366, 1273, 1242, 1200, 872, 752. 1H NMR spectrum, δ, ppm (J, Hz): 1.30 (9H, s, C(CH3)3); 1.75-1.83 (6H, m, 3СH2 Ad); 2.12 (9H, br. s, 3CH Ad, 3CH2 Ad); 3.38 (3H, s, NCH3); 3.66 (3H, s, NCH3); 3.73 (2H, s, 5-CH2); 7.06 (1H, d, J = 2.5) and 7.20 (1H, d, J = 2.5, H-6,8). 13C NMR spectrum, δ, ppm: 22.3 (5-CH2); 28.2 (NCH3); 28.9 (3CH Ad); 30.6 (NCH3); 31.5 (C(CH3)3); 34.7 (CMe3); 36.9 (3CH2 Ad); 37.2 (C Ad); 40.9 (3CH2 Ad); 85.5 (C-4a); 119.5 (C); 123.2 (CH); 124.6 (CH); 137.3 (C); 146.4 (C); 147.9 (C); 151.0 (C); 152.7 (C); 162.8 (C). Mass spectrum, m/z (I rel, %): 434 [M]+ (100), 419 [M-CH3]+ (15), 136 [C10H15]+ (13). Found, %: С 74.72; Н 7.82; N 6.35. C27H34N2O3. Calculated, %: С 74.62; Н 7.89; N 6.45.

1,3,7,8-Tetramethyl-1,5-dihydro-2 H -chromeno[2,3- d ]pyrimidine-2,4(3 H )-dione (3f≅. Yield 38%. Colorless crystals. Mp 239-240°С (EtOH). IR spectrum, ν, cm-1: 1701, 1665, 1643, 1584, 1503, 1487, 1449, 1323, 1302, 1273, 1223, 1202, 1042, 880, 758. 1H NMR spectrum, δ, ppm (J, Hz): 2.21 (3H, s, ArCH 3); 2.22 (3H, s, ArCH 3); 3.36 (3H, s, NCH3); 3.48 (3H, s, NCH3); 3.63 (2H, s, 5-CH2); 6.82 (1H, s) and 6.95 (1H, s, H-6,9). 13C NMR spectrum, δ, ppm: 19.1 (ArCH3); 19.6 (ArCH3); 21.5 (5-CH2); 28.2 (NCH3); 29.0 (NCH3); 85.6 (C-4a); 116.7 (C); 117.2 (CH); 130.3 (CH); 134.1 (C); 136.7 (C); 147.2 (C); 150.9 (C); 152.9 (C); 162.9 (C). Mass spectrum, m/z (I rel, %): 272 [M]+ (86), 271 (92), 270 (70), 257 [M-CH3]+ (38), 215 (100). Found, %: С 66.23; Н 5.90; N 10.18. C15H16N2O3. Calculated, %: С 66.16; Н 5.92; N 10.29.