An efficient catalyst-free chemoselective multicomponent reaction for the synthesis of pyrimidine functionalized pyrrolo-annelated derivatives

Abstract

An efficient method for the synthesis of pyrimidine functionalized pyrrolo-annelated derivatives has been developed via a catalyst-free, one-pot chemoselective multicomponent domino reaction. The method offers ease of execution, easy and column free separation, mild reaction conditions, and high yields.

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Introduction

Multicomponent reactions (MCRs) are alternative green techniques to multistep processes. Application of MCRs in the synthesis of natural products and building blocks are well documented in the literature.¹ MCRs have remarkable impact in the field of medicinal chemistry, combinatorial synthesis, and pharmaceutical industry due to their loftier gains like simplistic execution, convergence, less energy consumption, more productivity with excellent chemo and regio-selectivities.² Therefore, the design of new chemo- and regio-selective multicomponent reactions for easy and efficient synthesis is an ongoing challenge to synthetic chemists.³ In recent literature the number of reports regarding reagent and substrate based multicomponent reactions are quite high.⁴ Especially isocyanide based multicomponent reactions (IMCRs)⁵ and arylglyoxal based multicomponent reactions⁶ are well established for the construction of diverse molecular libraries in easy and efficient way.

Moreover, pyrrole core unit is present in many natural products, its analogues are renowned in medicine⁷ and many reports were published in recent literature⁸ to produce their novel analogues of indoles,⁹ carbazoles,¹⁰ pyrrolo pyrimidines,¹¹ indeno pyrroles,¹² and pyrrolo naphthoquinones.¹³ Pyrimidinylpyrrole motif appears in several natural and bioactive products like meridianins, variolins, psammopemmins, hyrtinadine, aplicyanins etc.¹⁴ and therefore, cyclic systems with this structural motif draw considerable attention in the field of combinatorial chemistry and drug discovery.¹⁵ In continuation to our studies towards the synthesis of pyrimidine heterocycles and drug intermediates via multicomponent reactions,¹⁶ herein we report an efficient chemoselective multicomponent one-pot strategy for the construction of novel pyrimidinylpyrrole fused cyclic systems under catalyst-free conditions using different cyclic 1,3-dicarbonyl compounds (Scheme 1).

Scheme 1 Synthesis of pyrimidine functionalized pyrrolo-annelated derivatives.

Results and discussion

We initiated our study by performing a one-pot reaction of 1,3-indanedione 1, 4-methoxy aniline 2a, 1,3-dimethyl barbituric acid 3a, and 4-methyl phenylglyoxal hydrate 4a in equimolar quantities using different solvents. It was found that ethanolic mixture of all the reactants under reflux conditions gave 5a in 89% yield. Other solvents like water (24%), toluene (39%), acetonitrile (59%), dimethylformamide (56%), chloroform (42%), acetic acid (64%), and methanol (79%) are comparatively less effective towards this transformation. Moreover, it is remarkable to note here that the reaction occurred at room temperature also but with a lesser yield (10%). A variation in temperature revealed that reflux condition is the best reaction condition for synthesis of the desired product. It was observed that the product 5-(1-(4-methoxyphenyl)-4-oxo-2-(p-tolyl)-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione 5a was formed exclusively without the formation of the other likely products 5(i) or 5(ii) (Scheme 2). The ¹H-NMR spectrum of 5a showed a singlet with 6 protons at 3.38 ppm. The N-methyl signal at 28.81 ppm in ¹³C-NMR clearly shows that methyl protons of barbituric acid are at the same chemical environment which indicates the formation of 5a. The chemoselective formation of enamine of 1,3-diketones 1 and 3a with aromatic amine 2a can explain the formation of 5a rather than 5(i) or 5(ii). Due to resonance of the amide nitrogen towards the carbonyl group, the reactivity of barbituric acid amide ketone is less than the ketone group of 1 to form the enamine intermediate with aromatic amine 2a, which lead to selective formation of 5a but not 5(i) or 5(ii).

Scheme 2 Chemoselective formation of pyrrolo-annelated derivative 5a.

The scope of the reaction was examined under optimized reaction conditions, with different substituted aromatic amines 2 and aromatic phenylglyoxal hydrates 4. The results obtained are summarized in Table 1. Generalization study reveals that the method is suitable with a wide variety of substituted aromatic amines and arylglyoxal hydrates with excellent yields (Table 1, entries 5a–k). The reaction was also equally effective with aromatic amines and phenylglyoxal hydrates containing both the electron-withdrawing and -donating groups. The products thus obtained were characterized by spectroscopic analyses.

Table 1 Chemoselective synthesis of 3-(pyrimidin-5-yl)indeno[1,2-b]pyrrol-4(1H)-one derivatives 5a–k^a

a Reaction conditions: indane-1,3-dione 1 (1 mmol), aromatic amine 2 (1 mmol), barbituric acid 3a (1 mmol) and phenylglyoxal hydrate 4 (1 mmol) was refluxed in 8 mL of ethanol for 30 min.

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Encouraged by the above results, we extended our study to find the feasibility of the method with other cyclic 1,3-dicarbonyl compounds viz. dimedone 6 and 2-hydroxy naphthoquinone 8 (Scheme 3). We found that under identical reaction condition the desired pyrimidinylpyrrole fused derivatives 7 and 9 were obtained in good yields without the formation of any other products. The generalization study for the formation of 7 is listed in Table 2. The scope of the reaction scheme was well tolerated with various substituted aromatic amines 2, barbituric acid 3 and arylglyoxal hydrate 4 and successfully furnished the corresponding pyrimidinylpyrrole fused analogues of 7a–l in good to excellent yields. Furthermore, we observed that the free NH group of 3b did not interrupt the reaction process, constructing the desired pyrimidinylpyrrole fused derivative in good yields (Scheme 3).

Scheme 3 Chemoselective formation of pyrrolo-annelated derivatives 7 & 9.

Table 2 Synthesis of 3-(pyrimidin-5-yl)-6,7-dihydro-1H-indol-4(5H)-one derivatives 7a–l^a

a Reaction conditions: dimedone 6 (1 mmol), aromatic amine 2 (1 mmol), barbituric acid 3 (1 mmol) and arylglyoxal hydrate 4 (1 mmol) was refluxed in 8 mL of ethanol for 30 min.

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We then performed the same reaction using 6-amino-1,3-dimethyluracil as enamine instead of in situ generated enamine of an aromatic amine and cyclic 1,3-dicarbonyl compound which generates enamine and we observed the formation of pyrimidinylpyrrole fused pyrimidine derivative in good yields. In a typical case, a mixture of 1,3-dimethyl-6-amino uracil 10a, 1,3-dimethyl barbituric acid 3a, and phenylglyoxal hydrate 4 in ethanol was refluxed with stirring for 30 min (monitored vide TLC). On completion, after usual work-up the desired pyrimidinylpyrrole fused pyrimidine derivative 11a was obtained in 88% yield. The reaction was then generalized by using different 6-amino uracil 10a–c, barbituric acid 3a–b, and arylglyoxal hydrates 4 to obtain the substrate scope of the reaction scheme (Table 3). The nature of substituent's in the substrates played no significant role towards the formation of the products and in all the cases reaction proceeds smoothly to give 11 as the product exclusively.

Table 3 Substrate scope for the synthesis of 3-(pyrimidin-5-yl)indeno[1,2-b]pyrrol-4(1H)-one derivatives 11a–j^a

a Reaction conditions: 6-aminouracil 10 (1 mmol), barbituric acid 3a (1 mmol) and phenylglyoxal hydrate 4 (1 mmol) was refluxed in 8 mL of ethanol for 30 min.

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Although the detailed mechanistic studies are not performed, a possible mechanism for the formation of pyrimidinylpyrrolo fused cyclic compounds is shown in Scheme 4. It is assumed that under reflux conditions 3 and 4 form Knoevenagel product A, which undergoes 1,3-dipolar cyclization with 6-amino uracil 10, leads to the formation of 11. Similarly, 1,3-dipolar cyclization of A with in situ generated enaminones B from cyclic 1,3-dicarbonyl compounds and aromatic amines forms other pyrrole fused ring systems 5 or 7 or 9.

Scheme 4 Plausible mechanism for the formation of pyrrolo-annelated derivatives.

To support our mechanistic postulate, we have carried out the reaction in three-component as well as two-component manner. In three component process, the reaction of 1,3-dimethylbarbituric acid 3a, phenylglyoxal hydrate 4a with enamine 12 (prepared from aromatic amine 2a and dimedone 6)¹⁷ under reflux conditions in ethanol was performed and got the desired product 7e. Moreover, the two component reaction of enamine 12 and Knoevenagel product 13 also resulted the product 7e under similar reaction conditions. Compound 13 was prepared from 3a and 4a by using procedure reported in the earlier literature.¹⁸ These experiments supports our assumption that the reaction was proceeded through in situ formation of an enamine and Knoevenagel products (Scheme 5).

Scheme 5 Mechanistic studies for the formation of 7e.

Conclusions

In conclusion, we have developed a facile and efficient one-pot ecofriendly multicomponent reaction strategy for the construction of pyrimidinyl functionalized pyrrole fused heterocycles. A variety of arylglyoxal hydrates have been shown to participate in a clean reaction with barbituric acid and enaminones or in situ generated enaminones from cyclic 1,3-dicarbonyl compounds and several aromatic amines under catalyst-free conditions. The methodology provides a rapid access to pyrimidinyl functionalized pyrrolo-annelated derivatives with excellent yields without tedious workup and purification processes. Further, we believe that our developed methodology will be a good alternative for the synthesis of pyrrole fused heterocycles.

Experimental

General experimental methods

Phenylglyoxal hydrates were prepared accordingly earlier reported procedure,¹⁹ remaining all the other commercially available reagents were used as received. IR Spectra were recorded on a SHIMADZU FTIR-8400 instrument. NMR spectra were recorded on Avance DPX 300 MHz FT-NMR spectrometer and Avance DPX 500 MHz FT-NMR using tetramethyl silane (TMS) as an internal standard. Mass spectra were recorded on ESQUIRE 3000 Mass spectrometer. All the experiments were monitored by thin layer chromatography (TLC). TLC was performed on pre-coated silica gel plates (Merck).

Typical procedure for the synthesis of pyrrolo-annelated derivatives (5 or 7 or 9)

1,3-Indanedione 1 (1 mmol), aromatic amine 2 (1 mmol), barbituric acid 3 (1 mmol), arylglyoxal hydrate 4 (1 mmol), and ethanol (8 mL) were taken in a 50 mL round bottom flask. The mixture was stirred at refluxing temperature for 30 min. After completion of the reaction, the reaction mixture was cooled, formed solids were filtered and washed with cold ethanol to obtain the products 5a–k.

Similarly, the reaction was carried out by taking dimedone 6 or 2-hydroxy-1,4-naphthoquinone 8 in place of indane-1,3-dione 1 to obtain 7 or 9.

5-(1-(4-Methoxyphenyl)-4-oxo-2-(p-tolyl)-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5a). Black solid (yield 89%); mp: 275.6–276.4 °C; IR (KBr, ν/cm⁻¹): 3431, 3052, 2966, 2845, 1693, 1633, 1605, 1519, 1446, 1374, 1287, 1253, 1118, 1029, 899, 868, 841, 828, 769, 751, 726, 654; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.28 (d, J = 7.2 Hz, 3H), 7.17 (d, J = 8.8 Hz, 2H), 7.09 (d, J = 7.9 Hz, 2H), 7.00 (dd, J = 5.2, 3.1 Hz, 2H), 6.88 (d, J = 8.9 Hz, 2H), 6.36 (dd, J = 5.2, 2.9 Hz, 1H), 4.52 (s, 1H), 3.83 (s, 3H), 3.38 (s, 6H), 2.31 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 186.09, 167.37, 159.54, 151.68, 151.37, 141.46, 139.08, 138.47, 135.82, 132.49, 130.56, 129.65, 129.25, 128.25, 128.14, 125.87, 123.46, 120.34, 117.48, 114.39, 112.47, 55.49, 46.59, 28.81, 21.32; MS (GCMS, m/z) 519.9 [M]⁺; anal. calcd for C₃₁H₂₅N₃O₅: C, 71.67; H, 4.85; N, 8.09; O, 15.39. Found C, 71.64; H, 4.86; N, 8.08; O, 15.42.

5-(1-(4-Methoxyphenyl)-4-oxo-2-phenyl-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5b). Black solid (yield 74%); mp: 295.0–295.8 °C; IR (KBr, ν/cm⁻¹): 3423, 3062, 2997, 2956, 2932, 2840, 1752, 1683, 1607, 1516, 1445, 1376, 1291, 1246, 1119, 1023, 987, 898, 886, 785, 757, 725, 708, 686; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.45–7.35 (m, 2H), 7.30 (dd, J = 7.5, 5.0 Hz, 4H), 7.17 (d, J = 8.8 Hz, 2H), 7.01 (dd, J = 5.1, 3.1 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.43–6.33 (m, 1H), 4.53 (s, 1H), 3.83 (s, 3H), 3.39 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): 186.06, 167.32, 159.59, 151.65, 151.49, 141.28, 139.06, 135.75, 132.54, 130.71, 129.55, 128.86, 128.53, 128.23, 123.50, 120.39, 117.56, 114.42, 112.65, 55.49, 46.55, 28.82; MS (GCMS, m/z) 505.9 [M]⁺; anal. calcd for C₃₀H₂₃N₃O₅: C, 71.28; H, 4.59; N, 8.31; O, 15.82. Found C, 71.26; H, 4.58; N, 8.33; O, 15.83.

5-(2-(4-Bromophenyl)-1-(4-methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5c). Red solid (yield 81%); mp: 299.8–300.6 °C; IR (KBr, ν/cm⁻¹): 3420, 3075, 2966, 2908, 2833, 1692, 1605, 1519, 1448, 1375, 1286, 1254, 1185, 1117, 1089, 1030, 983, 898, 868, 834, 812, 768, 753, 725, 654; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.43 (d, J = 8.4 Hz, 2H), 7.33–7.27 (m, 3H), 7.16 (d, J = 8.8 Hz, 2H), 7.02 (dd, J = 4.8, 3.5 Hz, 2H), 6.91 (d, J = 8.8 Hz, 2H), 6.38 (dd, J = 5.4, 2.7 Hz, 1H), 4.46 (s, 1H), 3.85 (s, 3H), 3.39 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): 185.93, 167.18, 159.75, 151.73, 151.58, 139.93, 138.96, 135.54, 132.62, 132.19, 131.81, 129.24, 128.39, 128.21, 127.82, 123.62, 123.07, 120.37, 117.66, 114.61, 112.98, 55.54, 46.50, 28.86; MS (GCMS, m/z) 584.8 [M]⁺; anal. calcd for C₃₀H₂₂BrN₃O₅: C, 61.66; H, 3.79; Br, 13.67; N, 7.19; O, 13.69. Found C, 61.64; H, 3.80; Br, 13.66; N, 7.18; O, 13.72.

5-(2-(4-Chlorophenyl)-1-(4-methoxyphenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5d). Red solid (yield 82%); mp: 279.8–280.6 °C; IR (KBr, ν/cm⁻¹): 3436, 2948, 2929, 1695, 1681, 1601, 1517, 1420, 1376, 1286, 1260, 1093, 1018, 840, 767, 726; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.38–7.25 (m, 5H), 7.16 (d, J = 8.8 Hz, 2H), 7.02 (dd, J = 5.0, 3.3 Hz, 2H), 6.90 (d, J = 8.8 Hz, 2H), 6.38 (dd, J = 5.5, 2.7 Hz, 1H), 4.46 (s, 1H), 3.85 (s, 3H), 3.39 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): 185.94, 167.20, 159.74, 151.70, 151.58, 139.93, 138.97, 135.56, 134.75, 132.61, 131.96, 129.26, 128.86, 128.38, 128.21, 127.35, 123.61, 120.35, 117.65, 114.59, 113.00, 55.53, 46.50, 28.85; MS (GCMS, m/z) 539.9 [M]⁺; anal. calcd for C₃₀H₂₂ClN₃O₅: C, 66.73; H, 4.11; Cl, 6.57; N, 7.78; O, 14.81. Found C, 66.74; H, 4.12; Cl, 6.56; N, 7.76; O, 14.82.

5-(2-(4-Methoxyphenyl)-4-oxo-1-(p-tolyl)-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5e). Red solid (yield 81%); mp: 298.6–299.4 °C; IR (KBr, ν/cm⁻¹): 3435, 3075, 2966, 2833, 1694, 1678, 1606, 1516, 1453, 1376, 1291, 1257, 1178, 1114, 1032, 985, 898, 844, 800, 768, 727; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.31 (t, J = 7.9 Hz, 3H), 7.15 (dd, J = 18.9, 8.3 Hz, 4H), 6.99 (dt, J = 7.8, 3.9 Hz, 2H), 6.81 (d, J = 8.7 Hz, 2H), 6.37 (dd, J = 5.2, 3.0 Hz, 1H), 4.50 (s, 1H), 3.77 (s, 3H), 3.38 (s, 6H), 2.38 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 186.10, 167.41, 159.71, 151.68, 151.06, 141.13, 139.04, 138.81, 135.86, 134.33, 132.47, 132.11, 129.91, 128.10, 126.86, 123.43, 121.13, 120.39, 117.52, 113.94, 112.51, 55.22, 46.60, 28.81, 21.22; MS (GCMS, m/z) 519.9 [M]⁺; anal calcd for C₃₁H₂₅N₃O₅: C, 71.67; H, 4.85; N, 8.09; O, 15.39. Found C, 71.64; H, 4.86; N, 8.09; O, 15.41.

1,3-Dimethyl-5-(4-oxo-1,2-di-p-tolyl-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (5f). Black solid (yield 70%); mp: 189.2–190.0 °C; IR (KBr, ν/cm⁻¹): 3428, 3023, 2960, 2925, 1694, 1679, 1633, 1603, 1516, 1495, 1453, 1417, 1373, 1286, 1261, 1187, 1117, 1088, 1022, 982, 898, 867, 837, 826, 767, 753, 727, 655; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.30–7.24 (m, 3H), 7.13 (dt, J = 10.9, 8.1 Hz, 6H), 6.99 (dd, J = 4.9, 3.2 Hz, 2H), 6.37 (dd, J = 4.9, 3.3 Hz, 1H), 4.52 (s, 1H), 3.38 (s, 6H), 2.38 (s, 3H), 2.31 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 186.12, 167.37, 151.69, 151.19, 141.31, 139.06, 138.82, 138.47, 135.84, 134.33, 132.49, 130.53, 129.90, 129.24, 128.13, 126.84, 125.89, 123.45, 120.50, 117.57, 112.57, 46.56, 28.81, 21.34, 21.23; MS (GCMS, m/z) 504.1 [M]⁺; anal. calcd for C₃₁H₂₅N₃O₄: C, 73.94; H, 5.00; N, 8.34; O, 12.72. Found C, 73.94; H, 5.01; N, 8.33; O, 12.72.

5-(2-(4-Chlorophenyl)-4-oxo-1-(p-tolyl)-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5g). Red solid (yield 68%); mp: 300.4–301.2 °C; IR (KBr, ν/cm⁻¹): 3432, 3057, 2961, 2916, 1695, 1678, 1604, 1505, 1458, 1377, 1288, 1117, 1087, 1015, 899, 844, 829, 766, 753, 728, 659; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.39–7.28 (m, 3H), 7.27 (d, J = 3.6 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.06–6.96 (m, 2H), 6.39 (dd, J = 5.4, 2.8 Hz, 1H), 4.46 (s, 1H), 3.39 (s, 6H), 2.40 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 185.95, 167.19, 151.58, 151.52, 139.80, 139.21, 138.96, 135.59, 134.75, 134.02, 132.59, 131.94, 130.11, 128.84, 128.37, 127.39, 126.80, 123.60, 120.51, 117.72, 113.10, 46.48, 28.85, 21.22; MS (GCMS, m/z) 523.9 [M]⁺; anal. calcd for C₃₀H₂₂ClN₃O₄: C, 68.77; H, 4.23; Cl, 6.77; N, 8.02; O, 12.21. Found C, 68.74; H, 4.24; Cl, 6.78; N, 8.01; O, 12.23.

5-(1-(4-Bromophenyl)-4-oxo-2-(p-tolyl)-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5h). Red solid (yield 83%); mp: 294.8–295.6 °C; IR (KBr, ν/cm⁻¹): 3431, 3057, 2960, 2914, 1694, 1679, 1603, 1505, 1456, 1376, 1288, 1117, 1087, 1015, 899, 842, 827, 766, 752, 726, 656; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.53 (d, J = 8.6 Hz, 2H), 7.32 (dd, J = 5.5, 2.8 Hz, 1H), 7.25 (d, J = 8.8 Hz, 2H), 7.12 (t, J = 7.8 Hz, 4H), 7.03 (dd, J = 4.7, 3.6 Hz, 2H), 6.41 (dd, J = 5.4, 2.7 Hz, 1H), 4.51 (s, 1H), 3.38 (s, 6H), 2.33 (s, 3H); ¹³C NMR (75 MHz, CDCl₃): 185.99, 167.18, 151.61, 150.88, 141.18, 138.88, 138.85, 136.00, 135.54, 132.63, 132.58, 130.54, 129.46, 128.68, 128.38, 125.46, 123.67, 122.78, 120.99, 117.45, 112.93, 46.49, 28.84, 21.33; MS (GCMS, m/z) 568.8 [M]⁺; anal. calcd for C₃₀H₂₂BrN₃O₄: C, 63.39; H, 3.90; Br, 14.06; N, 7.39; O, 11.26. Found C, 63.37; H, 3.91; Br, 14.05; N, 7.38; O, 11.29.

5-(1-(4-Chlorophenyl)-4-oxo-2-phenyl-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5i). Red solid (yield 69%); mp: 272.8–273.6 °C; IR (KBr, ν/cm⁻¹): 3435, 3059, 2960, 1693, 1680, 1605, 1505, 1445, 1378, 1291, 1262, 1192, 1093, 1017, 985, 926, 900, 867, 843, 809, 756, 727, 656; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.44–7.27 (m, 8H), 7.20 (d, J = 8.6 Hz, 2H), 7.08–6.99 (m, 2H), 6.49–6.33 (m, 1H), 4.52 (s, 1H), 3.37 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): 185.98, 167.15, 151.58, 151.08, 141.06, 138.84, 135.48, 135.39, 134.85, 132.67, 130.67, 129.64, 128.85, 128.74, 128.47, 128.37, 123.72, 120.98, 117.51, 113.06, 46.46, 28.86; MS (GCMS, m/z) 510.8 [M]⁺; anal. calcd for C₂₉H₂₀ClN₃O₄: C, 68.31; H, 3.95; Cl, 6.95; N, 8.24; O, 12.55. Found C, 68.29; H, 3.94; Cl, 6.96; N, 8.23; O, 12.58.

5-(1,2-Bis(4-chlorophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5j). Dark tan solid (yield 74%); mp: 315.6–316.4 °C; IR (KBr, ν/cm⁻¹): 3431, 3057, 2954, 2897, 1694, 1679, 1630, 1603, 1505, 1453, 1376, 1286, 1094, 1017, 984, 899, 868, 845, 836, 766, 754, 726; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 7.40 (d, J = 8.5 Hz, 2H), 7.31 (dd, J = 16.1, 9.6 Hz, 5H), 7.20 (d, J = 8.4 Hz, 2H), 7.11–6.99 (m, 2H), 6.49–6.35 (m, 1H), 4.45 (s, 1H), 3.39 (s, 6H); MS (GCMS, m/z) 544.8 [M]⁺; anal. calcd for C₂₉H₁₉Cl₂N₃O₄: C, 63.98; H, 3.52; Cl, 13.02; N, 7.72; O, 11.76. Found C, 63.96; H, 3.53; Cl, 13.01; N, 7.73; O, 11.77.

5-(2-(4-Chlorophenyl)-1-(4-nitrophenyl)-4-oxo-1,4-dihydroindeno[1,2-b]pyrrol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (5k). Red solid (yield 86%); mp: 307.3–308.1 °C; IR (KBr, ν/cm⁻¹): 3432, 3429, 3058, 2956, 2898, 1697, 1680, 1642, 1631, 1603, 1508, 1459, 1379, 1286, 1095, 1018, 985, 900, 868, 836, 768, 726, 755, 657; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 8.31 (d, J = 8.9 Hz, 2H), 7.45 (d, J = 8.8 Hz, 2H), 7.40–7.27 (m, 5H), 7.09 (dd, J = 5.1, 3.1 Hz, 2H), 6.46 (dd, J = 5.4, 2.7 Hz, 1H), 4.46 (s, 1H), 3.40 (s, 6H); ¹³C NMR (75 MHz, CDCl₃): 185.70, 166.80, 151.42, 150.95, 147.50, 142.00, 139.60, 138.49, 135.57, 135.00, 132.91, 131.88, 129.35, 128.95, 127.98, 126.57, 125.00, 124.10, 121.80, 117.55, 114.12, 46.31, 28.95; MS (GCMS, m/z) 555.8 [M]⁺; anal. calcd for C₂₉H₁₉ClN₄O₆: C, 62.77; H, 3.45; Cl, 6.39; N, 10.10; O, 17.29. Found C, 62.75; H, 3.46; Cl, 6.38; N, 10.11; O, 17.30.

5-(1-(4-Methoxyphenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7a). White solid (yield 82%); mp: 254.6–255.4 °C (260.0–261.0 °C); IR (KBr, ν/cm⁻¹): 3420, 3368, 3268, 3079, 3056, 3002, 2951, 2870, 1682, 1645, 1515, 1490, 1471, 1441, 1410, 1376, 1284, 1248, 1168, 1102, 1045, 1024, 983, 926, 847, 805, 795, 772, 754, 704, 651; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 7.29 (d, J = 6.3 Hz, 3H), 7.17 (dd, J = 9.7, 5.5 Hz, 4H), 6.95 (d, J = 8.8 Hz, 2H), 4.84 (s, 1H), 3.76 (s, 3H), 3.16 (s, 6H), 2.52 (s, 2H), 2.21 (s, 2H), 0.99 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 194.10, 168.18, 159.14, 152.46, 144.30, 136.88, 130.40, 130.07, 129.69, 129.31, 128.89, 128.30, 115.81, 114.87, 112.21, 55.78, 51.39, 47.85, 36.38, 35.73, 28.82, 28.53; MS (GCMS, m/z) 500.1 [M]⁺; anal. calcd for C₂₉H₂₉N₃O₅: C, 69.72; H, 5.85; N, 8.41; O, 16.02. Found C, 69.73; H, 5.86; N, 8.39; O, 16.02.

5-(1-(4-Methoxyphenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7b). White solid (yield 87%); mp: 292.4–293.2 °C; IR (KBr, ν/cm⁻¹): 3226, 3107, 2957, 2869, 2844, 1760, 1719, 1691, 1645, 1515, 1493, 1471, 1445, 1405, 1368, 1300, 1252, 1205, 1168, 1114, 1034, 931, 888, 843, 807, 772, 704, 653; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.14 (s, 2H), 7.34–7.22 (m, 3H), 7.19–7.10 (m, 4H), 6.95 (d, J = 8.9 Hz, 2H), 4.68 (s, 1H), 3.76 (s, 3H), 2.53 (s, 2H), 2.22 (s, 2H), 1.00 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.79, 169.72, 159.10, 151.69, 144.07, 137.06, 130.40, 130.10, 129.77, 129.30, 128.83, 128.20, 116.05, 114.86, 111.89, 55.79, 51.58, 47.57, 36.41, 35.72, 28.52; MS (GCMS, m/z) 471.9 [M]⁺; anal. calcd for C₂₇H₂₅N₃O₅: C, 68.78; H, 5.34; N, 8.91; O, 16.97. Found C, 68.76; H, 5.35; N, 8.90; O, 16.99.

5-(6,6-Dimethyl-4-oxo-2-phenyl-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7c). White solid (yield 76%); mp: 282.6–283.4 °C; IR (KBr, ν/cm⁻¹): 3421, 3075, 3043, 2956, 2931, 2871, 2729, 1693, 1679, 1645, 1568, 1542, 1518, 1445, 1418, 1378, 1286, 1259, 1215, 1178, 1157, 1103, 1073, 1045, 982, 929, 894, 847, 774, 756, 706, 677, 652; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 7.32–7.06 (m, 9H), 4.84 (s, 1H), 3.15 (s, 6H), 2.53 (s, 2H), 2.31 (s, 3H), 2.21 (s, 2H), 0.99 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 194.02, 168.04, 152.34, 143.98, 138.08, 136.60, 134.36, 130.26, 130.18, 129.93, 128.79, 128.19, 127.72, 115.84, 112.29, 51.27, 47.71, 36.31, 35.63, 28.70, 28.39, 20.93; MS (GCMS, m/z) 484.1 [M]⁺; anal. calcd for C₂₉H₂₉N₃O₄: C, 72.03; H, 6.04; N, 8.69; O, 13.24. Found C, 72.01; H, 6.05; N, 8.70; O, 13.23.

5-(6,6-Dimethyl-4-oxo-2-phenyl-1-(p-tolyl)-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7d). White solid (yield 75%); mp: 324.6–325.4 °C; IR (KBr, ν/cm⁻¹): 3414, 3220, 3103, 2957, 2871, 1759, 1720, 1694, 1645, 1515, 1493, 1405, 1367, 1287, 1257, 1204, 1111, 1049, 1033, 974, 930, 835, 803, 773, 725, 703, 653, 633; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.14 (s, 2H), 7.35–7.00 (m, 9H), 4.68 (s, 1H), 2.54 (s, 2H), 2.30 (s, 3H), 2.22 (s, 2H), 0.99 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.83, 169.70, 151.68, 143.88, 138.12, 136.90, 134.56, 130.37, 130.27, 130.09, 128.85, 128.21, 127.83, 116.20, 112.09, 51.56, 49.07, 47.55, 36.46, 35.73, 28.49, 21.05; MS (GCMS, m/z) 455.9 [M]⁺; anal. calcd for C₂₇H₂₅N₃O₄: C, 71.19; H, 5.53; N, 9.22; O, 14.06. Found C, 71.18; H, 5.53; N, 9.21; O, 14.08.

5-(6,6-Dimethyl-4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7e). White solid (yield 79%); mp: 315.0–315.8 °C; IR (KBr, ν/cm⁻¹): 3435, 3230, 3103, 2960, 2833, 1739, 1730, 1710, 1631, 1597, 1497, 1472, 1420, 1386, 1346, 1258, 1232, 1198, 1157, 1112, 1064, 1048, 798, 771, 711, 691, 653; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 7.65–6.95 (m, 10H), 4.85 (s, 1H), 3.16 (s, 6H), 2.55 (s, 2H), 2.22 (s, 2H), 0.99 (s, 6H); ¹³C NMR (126 MHz, DMSO-d₆): 194.07, 168.02, 152.34, 143.91, 136.89, 136.60, 130.26, 129.85, 129.71, 128.78, 128.62, 128.22, 128.01, 115.94, 112.39, 51.27, 47.71, 36.29, 35.65, 28.70, 28.38; MS (GCMS, m/z) 469.9 [M]⁺; anal. calcd for C₂₈H₂₇N₃O₄: C, 71.62; H, 5.80; N, 8.95; O, 13.63. Found C, 71.60; H, 5.81; N, 8.94; O, 13.65.

5-(6,6-Dimethyl-4-oxo-1,2-diphenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7f). White solid (yield 71%); mp: 344.2–345.0 °C; IR (KBr, ν/cm⁻¹): 3451, 3223, 3082, 2967, 2954, 2935, 2838, 2869, 1738, 1729, 1629, 1537, 1496, 1470, 1439, 1409, 1362, 1341, 1257, 1231, 1197, 1157, 1112, 1064, 1049, 1028, 1003, 945, 889, 819, 798, 772, 749, 711, 691, 653; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.14 (s, 2H), 7.55–7.02 (m, 10H), 4.69 (s, 1H), 2.56 (s, 2H), 2.23 (s, 2H), 1.00 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.88, 169.70, 152.60, 151.71, 143.79, 137.08, 136.87, 130.36, 130.02, 129.81, 128.85, 128.12, 116.28, 112.21, 51.55, 47.57, 36.40, 35.76, 28.50; MS (GCMS, m/z) 441.9 [M]⁺; anal. calcd for C₂₆H₂₃N₃O₄: C, 70.73; H, 5.25; N, 9.52; O, 14.50. Found C, 70.71; H, 5.26; N, 9.51; O, 14.52.

5-(1-(4-Bromophenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7g). Light pink solid (yield 84%); mp: 325.4–326.2 °C; IR (KBr, ν/cm⁻¹): 3432, 3083, 2959, 2871, 1684, 1659, 1556, 1494, 1471, 1412, 1392, 1374, 1287, 1255, 1159, 1092, 1064, 1015, 987, 882, 855, 810, 756, 738, 724, 710, 651; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 7.62 (d, J = 8.6 Hz, 2H), 7.32 (d, J = 6.8 Hz, 3H), 7.18 (t, J = 8.2 Hz, 4H), 4.86 (s, 1H), 3.15 (s, 6H), 2.58 (s, 2H), 2.22 (s, 2H), 0.99 (s, 6H); ¹³C NMR (126 MHz, DMSO-d₆): 194.13, 167.96, 152.31, 143.96, 136.44, 136.20, 132.67, 130.29, 130.11, 129.58, 128.95, 128.40, 121.67, 116.14, 112.65, 51.24, 47.68, 36.16, 35.67, 28.71, 28.35; MS (GCMS, m/z) 548.8 [M]⁺; anal. calcd for C₂₈H₂₆BrN₃O₄: C, 61.32; H, 4.78; Br, 14.57; N, 7.66; O, 11.67. Found C, 61.29; H, 4.78; Br, 14.56; N, 7.67; O, 11.70.

5-(1-(4-Bromophenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7h). White solid (yield 82%); mp: 321.6–322.4 °C; IR (KBr, ν/cm⁻¹): 3397, 3223, 3098, 2958, 2867, 1761, 1719, 1691, 1645, 1587, 1537, 1493, 1467, 1406, 1372, 1353, 1296, 1259, 1205, 1153, 1114, 1070, 1049, 1012, 970, 931, 888, 839, 810, 795, 773, 759, 725, 704, 685, 651; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.16 (s, 2H), 7.61 (d, J = 8.5 Hz, 2H), 7.38–7.25 (m, 3H), 7.16 (t, J = 7.6 Hz, 4H), 4.70 (s, 1H), 2.58 (s, 2H), 2.23 (s, 2H), 1.00 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.93, 169.62, 151.68, 143.85, 136.75, 136.40, 132.76, 130.42, 130.22, 129.74, 129.00, 128.43, 121.72, 116.51, 112.47, 51.54, 49.07, 47.52, 35.78, 28.46; MS (GCMS, m/z) 520.8 [M]⁺; anal. calcd for C₂₆H₂₂BrN₃O₄: C, 60.01; H, 4.26; Br, 15.36; N, 8.07; O, 12.30. Found C, 59.99; H, 4.25; Br, 15.37; N, 8.06; O, 12.33.

5-(1-(4-Chlorophenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7i). White solid (yield 68%); mp: 315.6–316.4 °C; IR (KBr, ν/cm⁻¹): 3435, 3098, 2956, 2874, 1698, 1682, 1649, 1579, 1542, 1496, 1473, 1415, 1375, 1283, 1258, 1090, 1046, 1014, 984, 845, 810, 774, 758, 726, 704, 650; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.14 (s, 2H), 7.48 (d, J = 8.6 Hz, 2H), 7.38–7.19 (m, 5H), 7.18–7.09 (m, 2H), 4.70 (s, 1H), 2.58 (s, 2H), 2.23 (s, 2H), 1.00 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.91, 169.62, 151.67, 143.89, 136.80, 135.98, 133.20, 130.42, 129.94, 129.82, 129.75, 128.99, 116.48, 112.43, 51.53, 47.51, 36.31, 35.77, 28.46; MS (GCMS, m/z) 476.8 [M]⁺; anal. calcd for C₂₆H₂₂ClN₃O₄: C, 65.62; H, 4.66; Cl, 7.45; N, 8.83; O, 13.44. Found C, 65.61; H, 4.65; Cl, 7.44; N, 8.84; O, 13.46.

5-(2-(4-Chlorophenyl)-6,6-dimethyl-4-oxo-1-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (7j). White solid (yield 83%); mp: 321.2–322.0 °C; IR (KBr, ν/cm⁻¹): 3432, 3097, 2957, 2869, 1693, 1688, 1646, 1580, 1539, 1493, 1468, 1412, 1375, 1354, 1288, 1259, 1092, 1048, 1013, 984, 839, 812, 776, 759, 726, 704, 685, 650; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.17 (s, 2H), 7.42 (t, J = 7.0 Hz, 3H), 7.35 (d, J = 7.7 Hz, 2H), 7.22 (d, J = 7.6 Hz, 2H), 7.13 (d, J = 7.1 Hz, 2H), 4.73 (s, 1H), 2.56 (s, 2H), 2.23 (s, 2H), 1.00 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 193.88, 169.58, 151.67, 144.06, 136.83, 135.64, 133.16, 132.11, 129.93, 128.95, 128.12, 116.36, 112.69, 51.54, 47.50, 36.39, 35.76, 28.46; MS (GCMS, m/z) 476.7 [M]⁺; anal. calcd for C₂₆H₂₂ClN₃O₄: C, 65.62; H, 4.66; Cl, 7.45; N, 8.83; O, 13.44. Found C, 65.61; H, 4.64; Cl, 7.45; N, 8.85; O, 13.45.

5-(1-(4-Chlorophenyl)-6,6-dimethyl-4-oxo-2-phenyl-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7k). White solid (yield 78%); mp: 310.4–311.2 °C; IR (KBr, ν/cm⁻¹): 3422, 3099, 3080, 2956, 2931, 2869, 1698, 1682, 1648, 1567, 1544, 1496, 1473, 1415, 1375, 1283, 1258, 1171, 1157, 1113, 1090, 1075, 1026, 984, 927, 884, 844, 810, 773, 758, 726, 704, 650; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 7.49 (d, J = 8.5 Hz, 2H), 7.29 (dd, J = 15.8, 7.4 Hz, 5H), 7.16 (d, J = 5.2 Hz, 2H), 4.86 (s, 1H), 3.16 (s, 6H), 2.58 (s, 2H), 2.22 (s, 2H), 0.99 (s, 6H); ¹³C NMR (126 MHz, DMSO-d₆): 194.12, 167.96, 152.32, 144.01, 136.49, 135.77, 133.15, 130.29, 129.83, 129.73, 129.59, 128.94, 128.39, 116.12, 112.61, 51.24, 47.69, 36.15, 35.67, 28.71, 28.36; MS (GCMS, m/z) 504.8 [M]⁺; anal. calcd for C₂₈H₂₆ClN₃O₄: C, 66.73; H, 5.20; Cl, 7.03; N, 8.34; O, 12.70. Found C, 66.71; H, 5.21; Cl, 7.02; N, 8.33; O, 12.73.

5-(1-(4-Chlorophenyl)-6,6-dimethyl-4-oxo-2-(thiophen-2-yl)-4,5,6,7-tetrahydro-1H-indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (7l). Light pink solid (yield 69%); mp: 301.3–302.1 °C; IR (KBr, ν/cm⁻¹): 3435, 3081, 2958, 2870, 1682, 1651, 1548, 1496, 1472, 1416, 1374, 1284, 1255, 1156, 1091, 1061, 1016, 984, 881, 854, 806, 757, 739, 725, 709, 652; ¹H NMR (500 MHz, DMSO-d₆): δ (ppm), 7.56 (dd, J = 18.3, 6.8 Hz, 3H), 7.35 (d, J = 8.6 Hz, 2H), 7.10–6.94 (m, 2H), 4.97 (s, 1H), 3.16 (s, 6H), 2.55 (s, 2H), 2.22 (s, 2H), 0.99 (s, 6H); MS (GCMS, m/z) 510.8 [M]⁺; anal. calcd for C₂₆H₂₄ClN₃O₄S: C, 61.23; H, 4.74; Cl, 6.95; N, 8.24; O, 12.55; S, 6.29. Found C, 61.21; H, 4.75; Cl, 6.94; N, 8.23; O, 12.56; S, 6.31.

5-(1-(4-Chlorophenyl)-4,9-dioxo-2-phenyl-4,9-dihydro-1H-benzo[f]indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (9a). Red solid (yield 61%); mp: 221.8–222.6 °C; IR (KBr, ν/cm⁻¹): 3400, 3197, 3082, 2955, 2596, 1685, 1624, 1618, 1596, 1572, 1520, 1494, 1452, 1380, 1358, 1333, 1288, 1241, 1186, 1125, 1089, 1032, 1015, 993, 948, 923, 871, 862, 824, 816, 793, 775, 757, 722, 692, 670, 662, 657; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 8.22 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.4 Hz, 1H), 7.75 (dt, J = 15.0, 5.5 Hz, 5H), 7.61–7.12 (m, 6H), 4.98 (s, 1H), 3.42 (s, 6H); ¹³C NMR (75 MHz, CDCl₃) 182.01, 173.07, 165.90, 160.61, 151.61, 151.37, 134.36, 133.72, 132.73, 132.58, 130.90, 129.26, 128.41, 128.09, 127.47, 127.13, 126.77, 112.15, 46.67, 29.21; MS (GCMS, m/z) 537.1 [M]⁺; anal. calcd for C₃₀H₂₀ClN₃O₅: C, 66.98; H, 3.75; Cl, 6.59; N, 7.81; O, 14.87. Found C, 66.96; H, 3.76; Cl, 6.57; N, 7.80; O, 14.91.

5-(1-(4-Methoxyphenyl)-4,9-dioxo-2-(p-tolyl)-4,9-dihydro-1H-benzo[f]indol-3-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (9b). Red solid (yield 57%); mp: 235.6–236.4 °C; IR (KBr, ν/cm⁻¹): 3401, 3198, 2955, 2599, 2298, 1685, 1621, 1608, 1596, 1569, 1520, 1492, 1452, 1380, 1359, 1333, 1241, 1125, 1090, 1032, 1015, 948, 923, 871, 862, 824, 816, 775, 757, 722, 692, 670, 662; ¹H NMR (300 MHz, CDCl₃): δ (ppm), 8.62 (d, J = 6.5 Hz, 1H), 8.09 (d, J = 7.6 Hz, 1H), 7.73–7.64 (m, 2H), 7.23–7.08 (m, 6H), 6.98 (d, J = 8.6 Hz, 2H), 4.94 (s, 1H), 3.88 (s, 3H), 3.42 (s, 6H), 2.36 (s, 3H); MS (GCMS, m/z) 547.1 [M]⁺; anal. calcd for C₃₂H₂₅N₃O₆: C, 70.19; H, 4.60; N, 7.67; O, 17.54. Found C, 70.17; H, 4.60; N, 7.68; O, 17.55.

Typical procedure for the synthesis of pyrrolo[2,3-d]pyrimidin derivatives (11a–11j)

Amino uracil 10 (1 mmol), barbituric acid 3 (1 mmol), phenylglyoxal hydrate 4 (1 mmol), and ethanol (8 mL) were taken in a 50 mL round bottom flask. The mixture was stirred at refluxing temperature for 30 min. After completion of the reaction, the reaction mixture was cooled, formed solids were filtered and washed with cold ethanol to obtain the products 11a–j.

5-(1,3-Dimethyl-2,4-dioxo-6-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (11a). White solid (yield 88%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3435, 3260, 3198, 3080, 3059, 3009, 2950, 1683, 1653, 1603, 1569, 1433, 1376, 1300, 1119, 1067, 1035, 978, 861, 793, 762, 754, 745, 708, 693, 680; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.94 (s, 1H), 7.77–7.23 (m, 5H), 5.17 (s, 1H), 3.51 (s, 3H), 3.17 (s, 6H), 3.13 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆): 168.16, 159.27, 152.38, 151.06, 142.88, 139.75, 131.66, 130.84, 129.29, 128.55, 128.45, 109.17, 97.27, 47.30, 31.12, 28.91, 27.87; MS (GCMS, m/z) 409.1 [M]⁺; anal. calcd for C₂₀H₁₉N₅O₅: C, 58.68; H, 4.68; N, 17.11; O, 19.53. Found C, 58.66; H, 4.69; N, 17.10; O, 19.55.

5-(1,3-Dimethyl-2,4-dioxo-6-phenyl-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11b). White solid (yield 86%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3395, 3223, 3088, 2948, 2885, 1708, 1689, 1652, 1603, 1567, 1509, 1497, 1448, 1410, 1365, 1322, 1276, 1256, 1231, 1190, 1125, 1068, 1048, 979, 922, 855, 818, 790, 768, 775, 743, 705, 675, 623, 605; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.88 (s, 1H), 11.21 (s, 2H), 7.65–7.31 (m, 5H), 5.02 (s, 1H), 3.50 (s, 3H), 3.16 (s, 3H); ¹³C NMR (126 MHz, DMSO-d₆): 169.60, 159.02, 151.53, 150.98, 139.56, 131.77, 130.77, 129.12, 128.59, 128.43, 128.22, 126.90, 108.79, 97.36, 46.89, 30.99, 27.66; MS (GCMS, m/z) 381.1 [M]⁺; anal. calcd for C₁₈H₁₅N₅O₅: C, 56.69; H, 3.96; N, 18.37; O, 20.98. Found C, 56.66; H, 3.97; N, 18.36; O, 21.01.

5-(6-(4-Methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (11c). White solid (yield 79%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3420, 3368, 3268, 3079, 3056, 3002, 2952, 2870, 1683, 1645, 1516, 1441, 1413, 1376, 1302, 1285, 1170, 1105, 1057, 1028, 983, 926, 847, 795, 772, 754, 745, 708, 693, 651; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.86 (s, 1H), 7.50 (d, J = 8.5 Hz, 2H), 7.08 (d, J = 8.6 Hz, 2H), 5.10 (s, 1H), 3.80 (s, 3H), 3.49 (s, 3H), 3.17 (s, 6H), 3.13 (s, 3H); MS (GCMS, m/z) 439.1 [M]⁺; anal. calcd for C₂₁H₂₁N₅O₆: C, 57.40; H, 4.82; N, 15.94; O, 21.84. Found C, 57.38; H, 4.81; N, 15.93; O, 21.88.

5-(6-(4-Methoxyphenyl)-1,3-dimethyl-2,4-dioxo-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11d). White solid (yield 84%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3391, 3226, 3108, 2956, 2872, 2845, 1718, 1707, 1691, 1651, 1604, 1569, 1514, 1492, 1451, 1409, 1366, 1302, 1254, 1208, 1191, 1169, 1114, 1037, 982, 932, 889, 843, 807, 780, 706, 673; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.80 (s, 1H), 11.20 (s, 2H), 7.49 (d, J = 7.9 Hz, 2H), 7.07 (d, J = 7.9 Hz, 2H), 4.95 (s, 1H), 3.80 (3, 3H), 3.49 (s, 3H), 3.16 (s, 3H); ¹³C NMR (75 MHz, DMSO-d₆): 169.79, 159.60, 159.12, 151.64, 151.10, 139.37, 131.87, 129.95, 123.29, 114.69, 108.03, 97.31, 55.74, 46.98, 31.08, 27.77; MS (GCMS, m/z) 411.1 [M]⁺; anal. calcd for C₁₉H₁₇N₅O₆: C, 55.47; H, 4.17; N, 17.02; O, 23.34. Found C, 55.43; H, 4.18; N, 17.03; O, 23.36.

1,3-Dimethyl-5-(4-oxo-6-phenyl-2-thioxo-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11e). White solid (yield 76%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3529, 3426, 3258, 3109, 3057, 2903, 1672, 1632, 1606, 1507, 1447, 1383, 1288, 1260, 1163, 1119, 1028, 990, 918, 803, 765, 699, 650; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 13.46 (s, 1H), 12.02 (s, 1H), 12.00 (s, 1H), 7.57 (d, J = 7.2 Hz, 2H), 7.53–7.39 (m, 3H), 5.15 (s, 1H), 3.16 (s, 6H); ¹³C NMR (75 MHz, DMSO-d₆): 172.96, 168.18, 158.35, 152.30, 139.32, 132.81, 130.42, 129.20, 128.74, 108.91, 101.33, 47.06, 28.89; MS (GCMS, m/z) 397.1 [M]⁺; anal. calcd for C₁₈H₁₅N₅O₄S: C, 54.40; H, 3.80; N, 17.62; O, 16.11; S, 8.07. Found C, 54.39; H, 3.80; N, 17.61; O, 16.13; S, 8.07.

5-(6-(4-Bromophenyl)-4-oxo-2-thioxo-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (11f). Light tan solid (yield 82%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3384, 3243, 3105, 3034, 2886, 2343, 1671, 1602, 1505, 1451, 1428, 1382, 1290, 1262, 1184, 1163, 1119, 1006, 989, 832, 811, 758, 717, 604; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 13.49 (s, 1H), 12.07 (s, 1H), 12.02 (s, 1H), 7.69 (d, J = 8.1 Hz, 2H), 7.50 (d, J = 8.1 Hz, 2H), 5.14 (s, 1H), 3.16 (s, 6H); ¹³C NMR (126 MHz, DMSO-d₆): 172.97, 167.92, 158.16, 152.13, 139.32, 131.98, 131.48, 130.60, 129.45, 121.89, 109.31, 101.24, 84.25, 46.86, 28.77; MS (GCMS, m/z) 474.9 [M]⁺; anal. calcd for C₁₈H₁₄BrN₅O₄S: C, 45.39; H, 2.96; Br, 16.78; N, 14.70; O, 13.44; S, 6.73. Found C, 45.37; H, 2.95; Br, 16.76; N, 14.71; O, 13.47; S, 6.74.

5-(6-(4-Bromophenyl)-4-oxo-2-thioxo-2,3,4,7-tetrahydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11g). Light tan solid (yield 74%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3385, 3181, 2369, 1674, 1615, 1428, 1250, 1147, 1123, 1077, 1007, 824, 780, 728, 605; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 12.03 (s, 1H), 12.00 (s, 1H), 11.81 (s, 1H), 11.27 (s, 2H), 7.68–7.65 (m, 2H), 7.48–7.45 (m, 2H), 5.01 (s, 1H); MS (GCMS, m/z) 448.9 [M]⁺; anal. calcd for C₁₆H₁₀BrN₅O₄S: C, 42.87; H, 2.25; Br, 17.83; N, 15.62; O, 14.28; S, 7.15. Found C, 42.84; H, 2.26; Br, 17.82; N, 15.63; O, 14.29; S, 7.16.

5-(2-Amino-4-oxo-6-phenyl-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)-1,3-dimethylpyrimidine-2,4,6(1H,3H,5H)-trione (11h). Light olive green solid (yield 68%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3474, 3382, 3109, 3043, 2914, 2870, 2788, 1679, 1633, 1556, 1432, 1380, 1327, 1317, 1288, 1267, 1250, 1179, 1157, 1124, 1108, 1076, 1041, 1022, 985, 928, 900, 874, 824, 796, 781, 753, 706, 693, 661; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.44 (s, 1H), 10.14 (s, 1H), 7.57 (d, J = 7.6 Hz, 2H), 7.45 (t, J = 7.5 Hz, 2H), 7.35 (t, J = 7.3 Hz, 1H), 6.28 (s, 2H), 5.10 (s, 1H), 3.16 (s, 6H); MS (GCMS, m/z) 380.1 [M]⁺; anal. calcd for C₁₈H₁₆N₆O₄: C, 56.84; H, 4.24; N, 22.10; O, 16.82. Found C, 56.82; H, 4.24; N, 22.10; O, 16.84.

5-(2-Amino-6-(4-bromophenyl)-4-oxo-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11i). Black solid (yield 75%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3427, 3382, 3181, 3042, 2916, 2871, 2369, 1678, 1617, 1514, 1429, 1326, 1311, 1290, 1255, 1179, 1147, 1123, 1098, 1078, 1002, 983, 926, 869, 825, 782, 729, 691, 657; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 11.45 (s, 1H), 11.18 (s, 2H), 10.25 (s, 1H), 7.63 (d, J = 8.3 Hz, 2H), 7.45 (d, J = 8.3 Hz, 2H), 6.27 (s, 2H), 4.97 (s, 1H); MS (GCMS, m/z) 431.9 [M]⁺; anal. calcd for C₁₆H₁₁BrN₆O₄: C, 44.57; H, 2.57; Br, 18.53; N, 19.49; O, 14.84. Found C, 44.55; H, 2.57; Br, 18.52; N, 19.48; O, 14.88.

5-(2-Amino-4-oxo-6-phenyl-4,7-dihydro-1H-pyrrolo[2,3-d]pyrimidin-5-yl)pyrimidine-2,4,6(1H,3H,5H)-trione (11j). Light olive green solid (yield 86%); mp: >350.0 °C; IR (KBr, ν/cm⁻¹): 3467, 3381, 3224, 3081, 2943, 2883, 2791, 1703, 1681, 1653, 1605, 1562, 1498, 1449, 1376, 1325, 1278, 1257, 1232, 1185, 1159, 1126, 1098, 1074, 1047, 983, 924, 886, 856, 824, 792, 776, 743, 705, 683, 651; ¹H NMR (300 MHz, DMSO-d₆): δ (ppm), 12.18 (s, 2H), 11.52 (s, 1H), 10.44 (s, 1H), 7.45 (d, J = 7.7 Hz, 2H), 7.32 (t, J = 7.6 Hz, 2H), 7.17 (t, J = 7.2 Hz, 1H), 6.17 (s, 2H), 5.15 (s, 1H); ¹³C NMR (75 MHz, DMSO-d₆): 170.13, 159.33, 153.27, 151.69, 151.59, 131.92, 131.24, 129.17, 127.92, 127.65, 106.90, 99.51, 47.18, 40.71, 40.44, 40.16, 39.88, 39.61, 39.33, 39.05; MS (GCMS, m/z) 352.1 [M]⁺; anal. calcd for C₁₆H₁₂N₆O₄: C, 54.55; H, 3.43; N, 23.85; O, 18.17. Found C, 54.53; H, 3.44; N, 23.84; O, 18.19.

Acknowledgements

We thank DST and CSIR, New Delhi for financial support to this work. YD thanks UGC, New Delhi for the award of a research fellowship. We also thank the Director, CSIR-NEIST, Jorhat, for his keen interest and constant encouragement.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra00796h

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