Introduction

Due to the increasing concern about various diseases, more attention of multidisciplinary scientists has focused on the development of new, more effective treatments and novel drug molecules. Hence, heterocyclic compounds have recently attracted much more interest because of their useful pharmacological and biological properties. One of these is pyrans which are found in natural sources. An important member of pyrans is 4H-chromenes which are bicyclic oxygen heterocycles formed as a result of the fusion of benzene ring with 5,6-positions of 4H-pyran ring. 4H-Chromenes have been evaluated to exhibit significant pharmacological potential in a broad range of applications in relation to anticancer [1], antiinflammatory [2], acetylcholinesterase (AChE) inhibitory [3], anti-rheumatic [4], neurodegenerative diseases (Alzheimer, Down syndrome, Schizophrenia and Huntington) [5, 6], antimicrobial [7], antibacterial [8,9,10], antifungal properties [8, 11], and so on. They are also useful in fluorescence, pigment, optical, cosmetic, and agricultural applications [12]. Several methods have been reported for development of different catalysts under various conditions for one-pot, multicomponent synthesis of numerous 2-amino-3-cyano-4H-pyran derivatives due to their versatility and superior biological properties [5, 13,14,15,16,17,18].

Another important class of these heterocyclic compounds is imidazo[1,2-a]pyrimidines which are formed as a result of the fusion of imidazole and pyrimidine moieties. Imidazo[1,2-a]pyrimidines were evaluated to exhibit significant therapeutic potential linked to anticancer [19,20,21], cardiovascular [22], antibacterial [23], antimicrobial [21, 24], antifungal [25], antiviral [26], anti-inflammatory [27], HIV inhibitor [28], local anesthetic [29], P38 MAP kinase inhibitor properties [30] and in some agrochemicals [21, 31,32,33,34]. Many commercially available drugs, such as fasiplon, taniplon, and divaplon which are anxiolytic and anticonvulsant agents contain imidazo[1,2-a]pyrimidine moiety [35,36,37] (Fig. 1).

Fig. 1
figure 1

Structures of pharmacologically useful imidazo[1,2-a]pyrimidines and 4H-pyrans

Full size image

Multicomponent reactions (MCRs) are the beneficial and practical tools to synthesize complex functional heterocyclic scaffolds which combine three or more readily available starting materials through an one-pot approach. These types of reactions provide a lot of advantages such as rapid and selective product formation, high atom economy, low cost, minimum waste, and environmental friendliness compared with conventional multi-step reactions [38, 39].

Considering the remarkable medicinal applications of imidazo[1,2-a]pyrimidines and pyrans, the combination of these two scaffolds in a single molecule could be an important starting point for drug research. Some examples of the most active imidazo[1,2-a]pyrimidine and pyran compounds are presented in Fig. 1.

Herein, a simple and efficient procedure is reported for the synthesis of imidazo[1,2-a]pyrimidine-based pyran derivatives via one-pot three component reaction of imidazo[1,2-a]pyrimidine-2-carbaldehyde, malononitrile, and enolizable C–H activated acidic compounds in the presence of sodium carbonate in water or a mixture of ethyl alcohol/water as solvent at room temperature conditions (Scheme 1). All the products were fully characterized with various spectral analyses including FT-IR, 1H NMR, 13C NMR, and MS. It is expected that the studied molecules including two different pharmacophores show good prospective biological and pharmacological activities.

scheme 1

Results and discussion

Initially, imidazo[1,2-a]pyrimidine-2-carbaldehyde as starting material was obtained in a two-step synthetic procedure using the Chichibabin method as described in the literature [40] and the structure of the compound was compared with reported spectral data [40, 41]. While the first step is a condensation reaction with 2-aminopyrimidine and 1,1,3-trichloroacetone in THF, the second step consists of a hydrolysis reaction of the HCl salt of the fused biheterocycle with sodium acetate in water.

Then, the main investigation was initiated with a one-pot, multicomponent reaction of imidazo[1,2-a]pyrimidine-2-carbaldehyde (1), malononitrile (2), and resorcinol (3a) which was selected as a model reaction to synthesize compound 4a (Table 1). First, the conditions consisted of sodium carbonate (0.45 eq.) in H2O/EtOH as a solvent mixture at 25 °C ambient temperature for 24 h which resulted in 53% yield of product 4a according to the modified method in Ref. [8] (Table 1, entry 1). When using distilled water alone as solvent with the same amount of Na2CO3, the reaction completed in 16 h at room temperature with same moderate yield, 53% due to the limited base (Table 1, entry 3). It was observed that the product yield was decreased to 39% with 75 °C heating of the EtOH/H2O solvent mixture with the same amount of Na2CO3 (Table 1, entry 2). While the reflux conditions of 0.45 equiv. Na2CO3 in water resulted in 3 h reaction time and 60% yield, the reflux conditions of 1.3 equiv. Na2CO3 in water gave 1 h reaction time and 24% yield (Table 1, entries 4 and 6). Increasing the quantity of sodium carbonate to 1.3 equiv. resulted in a significantly higher yield (83%) and shorter reaction time (2 h) (Table 1, entry 5). Furthermore, a nitrogen containing organic base, piperazine (30% mol), was used instead of sodium carbonate to investigate the effect of base type (Table 1, entries 7, 8). The room temperature reaction was completed in a long time (48 h) and led to moderate yield of 4a, 51% (Table 1, entry 7). Increasing the reaction temperature led to a shortening of time to 3 h and also decreased the product yield, 40% (Table 1, entry 8). Microwave irradiation (50 W and 30 °C) was applied to the reaction mixture of model compound 4a and product was obtained in 12 min with 56% yield (Table 1, entry 9). When microwave energy (200 W) was irradiated at 70 °C, it was observed that the reaction completed in 20 min but the yield decreased to 61% compared to the best result (Table 1, entry 10). Consequently, increasing the temperature of the EtOH/H2O mixture or only H2O in the presence of sodium carbonate or piperazine resulted lower yields of 4a due to the formation of new by-products (Table 1, entries 2, 6, 8, and 10). When all outputs are evaluated, the best result was obtained using 1.0 equiv. imidazo[1,2-a]pyrimidine-2-carbaldehyde, 1.3 equiv. malononitrile, 1.3 equiv. resorcinol, and 1.3 equiv. sodium carbonate in H2O at room temperature. The optimization results of 4a are shown in Table 1.

Table 1 Optimization of the reaction conditions for the synthesis of 2-amino-7-hydroxy-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-chromene-3-carbonitrile (4a)
figure a
Full size table

After reaching optimum conditions, various phenol derivatives (resorcinol, 3-aminophenol, orcinol, 4-chlororesorcinol, pyrogallol, and 1-naphthol) were utilized in the optimized one-pot multicomponent reaction conditions and the corresponding products 4a–4f were successfully obtained in short reaction times (2–7 h) and moderate to high yields (59–83%) at room temperature (Scheme 2). Furthermore, dimedon as an enolizable C–H activated acidic compound was also used as substrate in the optimized conditions and the desired product 4g was synthesized with 60% yield. It was observed that compounds 4b and 4f have longer reaction times (5 and 7 h, respectively) than other compounds (2–3 h) due to the partially lower reactivity of 3-aminophenol and 1-naphthol. In addition, when phenol or phenol derivatives containing electron-withdrawing functional groups such as 4-chlorophenol, 2-, 3-, 4-nitrophenols, or 4-nitrocatechol, were used as enolizable components, reactions occurred inefficiently with long reaction times and the desired pyran products were observed to have very low yields (< 10%). According to the TLC tracking, the first step occurs smoothly and the common condensation product forms successfully. However, one of the following steps fails due to the unstable intermediates caused by electron-withdrawing functional groups and the final pyran compounds could not be obtained efficiently. All the synthesized final products are novel and were fully characterized with their analytical data and spectral analyses including FT-IR, 1H NMR, 13C NMR, and MS (see “Experimental” section and Supplementary data).

scheme 2

Mechanistically, the final products are obtained in three main steps including Knoevenagel condensation, Michael addition, and heterocyclization reactions, respectively, similar to the data reported in the literature [5, 16, 17]. Based on this approach, the reaction starts with the formation of carbanion intermediate I from malononitrile-active methylene compound and the attack of this intermediate to the carbonyl of imidazo[1,2-a]pyrimidine-2-carbaldehyde to form the olefin intermediate II as Knoevenagel product. In the second step, Michael type addition occurs between intermediate II and sodium phenolate derivatives which is formed by phenol derivatives and sodium carbonate to give intermediate III as addition product. Cyclization starts with deprotonation by base on intermediate III and following a series of intramolecular rearrangements result in formation of the aromatic intermediate IV which produced the desired heterocyclic products (imidazo[1,2-a]pyrimidine-based pyrans 4a–4g) through imine-enamine tautomerization. The importance of sodium carbonate as base in the mechanism can be observed clearly at three points which are deprotonation of the active methylene compound at the beginning of the mechanism, formation the enolate intermediate of phenol derivatives and deprotonation of intermediate III to initiate cyclization. A plausible mechanism for the formation of imidazo[1,2-a]pyrimidine-based 4H-pyrans is shown in Scheme 3.

scheme 3

The spectra and values of products 4a–4g are given in the Experimental section and Supplementary data. In brief, all compounds exhibited N–H stretching and bending bands of -NH2 group at 3448–3303 cm−1 and 1658–1645 cm−1 in FT-IR spectra. The other major feature of the compounds was strong cyano (–CN) band at 2197–2185 cm−1 in the triple bond stretch region. In addition, aromatic C–H stretching and bending bands were generally at 3190–3006 cm−1 and 1620–1611 cm−1 frequency range, respectively. In addition, C=N and C=C stretching bands of imidazo[1,2-a]pyrimidine were in a similar range, 1658–1645 cm−1. While aliphatic C–H stretching absorption of the pyran ring was observed at 2990–2863 cm−1 as weak peak, C–O–C stretching band of pyran was determined at 1168–1139 cm−1 as strong peak. Other functional groups of varying compounds were monitored in expected regions of the IR spectra.

If the model compound 4a is examined spectroscopically in detail, peaks were observed in the range of 9.86–5.41 ppm on 1H NMR spectrum (Table 2). A total of four singlet peaks, three of them corresponding 1H integration and one peak corresponding 2H integration, were detected. The characteristic singlet peak with 2H integration at 7.10 ppm belongs to NH2 group. The broad singlet signal which was in the low-field part of the 1H NMR spectrum (9.86 ppm) confirms the presence of -OH group. The lowest singlet chemical shift (5.41 ppm) belongs to H-4 proton of the pyran ring. Therefore, the last singlet peak at 7.63 ppm corresponds to H-7ı proton of imidazole unit in the imidazo[1,2-a]pyrimidine ring. The other non-singlet aromatic peaks of pyrimidine and chromene rings were confirmed by two-dimensional NMR analysis. In the 13C NMR spectrum, the signals of C-3 and C-4 of the pyran unit were located in the high-field part of the spectrum (52.30 and 30.56 ppm, respectively). The other 14 carbons were observed in the region of 161.41–103.04 ppm as expected (Table 3).

Table 2 1H NMR and 1H-1H COSY data for compound 4a
figure b
Full size table
Table 3 13C NMR, HSQC, and HMBC data for compound 4a
Full size table

In addition, to determine the exact structure of compound 4a, two-dimensional homonuclear (1H-1H COSY) and heteronuclear correlation analyses (1H–13C HSQC and HMBC) were performed. Signal assignments of 1H, 13C and two-dimensional NMR correlations for compound 4a are presented in Tables 2 and 3. According to COSY spectrum, the three doublets of doublets peak at 7.04, 8.48, and 8.52 ppm in the low-field of spectrum are correlated with each other, which were assigned as H-5ı, H-4ı, and H-6ı of pyrimidine unit, respectively. HMBC results also confirmed this view about protons H-5ı, H-4ı, and H-6ı. In addition, chemical shifts at 6.73 ppm (1H) and 6.46 ppm (2H) had COSY correlation with each other, which were assigned as H-5, H-6, and H-8 of phenyl unit in the chromene ring, respectively. Protons H-6 and H-8 attached to the -OH containing carbon atom overlapped with 2H integration as a multiplet peak. According to HSQC interactions, it was concluded that signals at 150.00, 134.00, 132.59, 129.27, 113.17, 109.23, 103.04, and 30.56 ppm corresponded to carbons C-6ı, C-7ı, C-4ı, C-5, C-8, C-5ı, C-6, C-4, respectively (Table 3). Chemical shifts of carbons C-6 and C-8 were determined as a result of the extra HMBC correlation of C-6 with proton H-5. In addition, carbon C-2 gave HMBC correlation with -NH2 group and proton H-4 at the highest chemical shift, 161.41 ppm. The second highest value, 158.20 ppm, belongs to carbon C-7 due to the HMBC correlation with C-5 and -OH group. While carbon C-2aı at 148.58 ppm gave HMBC correlation with only proton H-7ı, the carbon of -CN group at 120.40 ppm correlates with only proton H-4. Ipso-carbon of imidazole ring (C-1ı) correlates with protons H-7ı and H-4 at 125.14 ppm. On the other hand, carbons C-4a and C-8a in the fused zone of the chromene unit were observed at 109.90 and 149.81 ppm due to the correlations with protons H-4, H6/H8 (for C-4a) and protons -NH2, H-4, H-5 and H-8 (for C-8a).

According to the positive mode of the LC–MS spectrum for model compound 4a contains the highest peak intensity (100%) of the molecular ion (m/z = 306, C16H11N5O2). The first fragmentation (m/z = 279) with 40% relative intensity is probably formed by the elimination of the cyano group. In addition, other final products were confirmed with the observation of their molecular ion peaks in the LC–MS spectra.

Conclusion

In summary, a simple and efficient one-pot, multicomponent synthesis method was developed for the potential biologically active novel imidazo[1,2-a]pyrimidine-based pyran derivatives 4a–4g from imidazo[1,2-a]pyrimidine-2-carbaldehyde, malononitrile, and enolizable C–H activated acidic components in the presence of sodium carbonate using water or a mixture of ethyl alcohol/water as solvent under room temperature conditions. The applied method has some privileged advantages such as mild reaction conditions, simple work-up and purification techniques, and moderate to good product yields (59–83%). The structures of all newly-synthesized compounds were elucidated by melting point, FT-IR, 1H NMR, 13C NMR, and MS spectra. The biological studies of novel imidazo[1,2-a]pyrimidine-based pyran analogs 4a–4g are ongoing in our research group.

Experimental

Commercially available reagents and solvents (Sigma-Aldrich, Merck, ABCR, Alfa Aesar, TCI, VWR, and Acros) were used without further purification. Melting points were determined by X-4 melting point apparatus. Thin layer chromatography was carried out using aluminum plates coated with Kieselgel silica gel 60GF254. Analyses were performed by visualizing under UV light (λ = 254 and 366 nm) and KMnO4 stain. IR spectra were recorded using Perkin Elmer Spectrum 100 FTIR spectrophotometer. 1H and 13C spectra were recorded using Jeol 400 MHz NMR spectrometer with DMSO-d6 as the analysis solvent. 1H, 13C, COSY, HMBC, and HSQC analyses of compound 4a were obtained using Agilent 600 MHz High-Performance Digital FT-NMR spectrometer. The chemical shifts are presented in ppm using TMS as an internal reference. Multiplicity (s: singlet, d: doublet, dd: doublet of doublet, t: triplet, q: quartet, m: multiplet) and coupling constants (J: Hz) are quoted where possible. The molecular weights of final products were determined with a Shimadzu LC–MS/MS 8040 Liquid Chromatograph Mass Spectrometer using an ESI source. CEM SP Discover Microwave Synthesis Reactor was used for the microwave experiments.

General procedure for synthesis of compounds 4a–4g

Imidazo[1,2-a]pyrimidine-2-carbaldehyde [40] (100 mg, 0.68 mmol, 1.0 equiv.), 58 mg malononitrile (0.88 mmol, 1.3 equiv.), and enolizable compounds (0.88 mmol, 1.3 equiv.) were dissolved in 5 cm3 water or a mixture of water:ethyl alcohol (4:1). Sodium carbonate (0.88 mmol, 93 mg, 1.3 equiv.) in 2 cm3 water was added and the mixture was stirred at room temperature for various times (2–7 h). The reaction process was monitored with thin layer chromatography using different ratio of hexane:ethyl acetate mixture as solvent. After completion of the reaction, the mixture was poured into brine solution and stirred for 15 min. The resulting solid was suction filtered using filter paper with small pore size and washed with water. The pure products 4a–4g were obtained by crystallization or washing with various solvents. Products were stored under argon atmosphere to prevent decomposition.

2-Amino-7-hydroxy-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-chromene-3-carbonitrile (4a, C16H11N5O2)

Using resorcinol in water with 2 h reaction time. The pure product 4a was obtained by crystallization with toluene/ethyl alcohol. Cream-colored solid; yield: 0.17 g (83%); m.p.: > 300 °C (dec.); 1H NMR (600 MHz, DMSO-d6): δ = 9.86 (1H, s), 8.52 (1H, dd, J = 3.90, 1.89 Hz), 8.48 (1H, dd, J = 6.88, 1.61 Hz), 7.63 (1H, s), 7.11 (2H, s), 7.04 (1H, dd, J = 4.1, 2.73 Hz), 6.73 (1H, t, J = 4.55 Hz), 6.46 (2H, m), 5.41 (1H, s) ppm; 13C NMR (150 MHz, DMSO-d6): δ = 161.41, 158.20, 150.00, 149.81, 148.58, 134.00, 132.59, 129.27, 125.14, 120.40, 113.17, 109.90, 109.23, 103.04, 52.30, 30.56 ppm; IR (ATR): \(\overline{v}\)  = 3477, 3384, 3337, 3187, 3094, 2990, 2919, 2185, 1651, 1617, 1592, 1497, 1398, 1318, 1279, 1139, 1111, 1037, 911, 874, 839, 788, 773, 699, 667 cm−1; MS: m/z (%) = 306 (M+, 100), 279 (40), 206 (36), 180 (36).

2,7-Diamino-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-chromene-3-carbonitrile (4b, C16H12N6O)

Using 3-aminophenol in water:ethyl alcohol with 5 h reaction time. The pure product 4b was obtained by washing with hot ethyl acetate. Brown solid; yield: 0.144 g (70%); m.p.: > 300 °C; 1H NMR (400 MHz, DMSO-d6): δ = 8.49 (1H, dd, J = 4.04, 1.91 Hz), 8.39 (1H, dd, J = 6.91, 1.90 Hz), 7.60 (1H, s), 7.00 (1H, dd, J = 6.89, 4.10 Hz), 6.97 (2H, s, broad), 6.53 (1H, d, J = 8.25 Hz), 6.24–6.20 (2H, m), 5.32 (2H, s, broad), 5.27 (1H, s) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 161.66, 150.10, 149.97, 149.94, 148.67, 133.96, 132.57, 128.83, 125.46, 120.63, 111.87, 109.22, 105.85, 100.68, 52.49, 30.75 ppm; IR (ATR): \(\overline{v}\) = 3404, 3320, 3188, 3096, 3041, 3006, 2190, 1647, 1614, 1570, 1511, 1495, 1454, 1389, 1339, 1229, 1168, 1140, 1067, 1032, 973, 846, 787 cm−1; MS: m/z (%) = 305 (M+, 100), 279 (48), 157 (20).

2-Amino-7-hydroxy-4-(imidazo[1,2-a]pyrimidin-2-yl)-5-methyl-4H-chromene-3-carbonitrile (4c, C17H13N5O2)

Using orcinol in water with 2 h reaction time. The pure product 4c was obtained by washing with hot toluene. Cream-colored solid; yield: 0.175 g (81%); m.p.: 283–285 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.80 (s, 1H), 8.90 (dd, J = 7.05, 1.98 Hz, 1H), 8.47 (dd, J = 4.08, 1.94 Hz, 1H), 7.31 (s, 1H), 7.07 (dd, J = 6.90, 4.08 Hz, 1H), 6.95 (s, 2H), 6.36 (s, 1H), 6.30 (s, 1H), 5.28 (s, 1H), 2.15 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 161.16, 155.46, 150.04, 149.37, 147.57, 139.13, 133.28, 132.97, 127.79, 120.98, 112.16, 108.78, 107.64, 106.02, 54.36, 26.63, 21.37 ppm; IR (ATR): \(\overline{v}\) = 3414, 3318, 3202, 3177, 3129, 3102, 3018, 2972–2863, 2186, 1645, 1580, 1504, 1398, 1337, 1298, 1257, 1146, 1079, 1050, 865, 829, 768, 726 cm−1; MS: m/z (%) = 320 (M+, 100), 310 (32), 279 (24), 171 (28).

2-Amino-6-chloro-7-hydroxy-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-chromene-3-carbonitrile (4d, C16H10ClN5O2)

Using 4-chlororesorcinol in water:ethyl alcohol with 2 h reaction time. The pure product 4d was obtained by washing with hot toluene/ethyl alcohol mixture. Light orange solid; yield: 0.155 g (67%); m.p.: > 300 °C (dec.); 1H NMR (400 MHz, DMSO-d6): δ = 10.65 (1H, s), 8.54–8.51 (2H, m), 7.59 (1H, s), 7.12 (2H, s, broad), 7.04 (1H, dd, J = 6.82, 4.16 Hz), 6.90 (1H, J = 0.7 Hz, d), 6.66 (1H, s), 5.41 (1H, s) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 161.30, 153.78, 150.23, 148.70, 148.47, 134.19, 132.75, 129.00, 125.00, 120.23, 116.61, 111.64, 109.42, 104.49, 52.42, 30.43 ppm; IR (ATR): \(\overline{v}\) = 3448, 3323, 3190, 3129, 3108, 2197, 1656, 1583, 1501, 1389, 1283, 1227, 1145, 1065, 876, 800, 785, 748, 700 cm−1; MS: m/z (%) = 340 (M+, 76), 327 (28), 300 (100), 279 (52).

2-Amino-7,8-dihydroxy-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-chromene-3-carbonitrile (4e, C16H11N5O3)

Using pyrogallol in water with 2 h reaction time. The pure product 4e was obtained by washing with hot toluene. Brown solid; yield: 0.173 g (79%); m.p.: > 195 °C (dec.); 1H NMR (400 MHz, DMSO-d6): δ = 8.49 (dd, J = 4.08, 1.96 Hz, 1H), 8.43 (dd, J = 6.92, 1.97 Hz, 1H), 7.60 (s, 1H), 7.01 (dd, J = 6.89, 4.1 Hz, 1H), 6.95 (s, 2H), 6.44 (d, J = 8.4 Hz, 1H), 6.15 (d, J = 8.4 Hz, 1H), 5.37 (s, 1H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 161.71, 150.01, 148.67, 146.20, 139.05, 134.00, 133.90, 132.65, 125.57, 120.54, 117.10, 112.41, 111.40, 109.25, 52.51, 31.08 ppm; IR (ATR): \(\overline{v}\) = 3363, 3179, 3087, 2188, 1648, 1611, 1589, 1519, 1485, 1400, 1300, 1203, 1152, 1084, 1062, 944, 874, 782, 762, 719 cm−1; MS: m/z (%) = 322 (M+, 100), 310 (16), 279 (40), 180 (30).

2-Amino-4-(imidazo[1,2-a]pyrimidin-2-yl)-4H-benzo[h]chromene-3-carbonitrile (4f, C20H13N5O)

Using 1-naphthol in water:ethyl alcohol with 7 h reaction time. The pure product 4f was obtained by crystallization with toluene/ethyl alcohol mixture. Light brown solid; yield: 0.135 g (59%); m.p.: > 209 °C (dec.); 1H NMR (400 MHz, DMSO-d6): δ = 8.58 (1H, dd, J = 6.93, 1.94 Hz), 8.50 (1H, dd, J = 4.12, 1.91 Hz), 8.26 (1H, d, J = 7.96 Hz), 7.88 (1H, d, J = 7.92 Hz), 7.66 (1H, s), 7.60–7.56 (2H, m), 7.33 (2H, s, broad), 7.08 (1H, m), 7.02–6.99 (2H, m), 5.70 (1H, s) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 161.37, 150.23, 148.73, 144.05, 134.51, 133.67, 132.71, 129.43, 128.74, 127.42, 125.85, 125.42, 125.05, 124.91, 123.28, 121.39, 114.56, 109.46, 52.62, 31.52 ppm; IR (ATR): \(\overline{v}\) = 3350, 3306, 3149, 3055, 2188, 1655, 1616, 1572, 1516, 1494, 1371, 1260, 1187, 1143, 1104, 797, 764, 732 cm−1; MS: m/z (%) = 340 (M+, 100), 329 (32), 300 (24), 279 (66).

2-Amino-4-(imidazo[1,2-a]pyrimidin-2-yl)-7,7-dimethyl-5-oxo-5,6,7,8-tetrahydro-4H-chromene-3-carbonitrile (4g, C18H17N5O2)

Using dimedone in water:ethyl alcohol with 3 h reaction time. After completion of the reaction, the mixture was poured into brine solution but solid formation was not observed. Therefore, the mixture was extracted with ethyl acetate (3 × 15 cm3), the organic phase was washed with water, dried with anhydrous Na2SO4 and evaporated in vacuo. The oily crude product was solidified using diethylether and crystallized with toluene to give 4g. Light orange solid; yield: 0.136 g (60%); m.p.: 145–149 °C; 1H NMR (400 MHz, DMSO-d6): δ = 9.09 (dd, J = 6.99, 1.88 Hz, 1H), 8.49 (dd, J = 4.06, 1.90 Hz, 1H), 7.44 (s, 1H), 7.13 (s, 2H), 7.09 (dd, J = 6.92, 4.08 Hz, 1H), 4.95 (s, 1H), 2.50 (s, 2H), 2.19, 2.10 (s, 2H), 1.00 (s, 3H), 0.91 (s, 3H) ppm; 13C NMR (100 MHz, DMSO-d6): δ = 196.86, 163.33, 159.28, 149.75, 147.62, 133.71, 133.09, 127.48, 120.11, 111.37, 108.80, 55.96, 50.40, 32.36, 28.59, 27.47, 25.18 ppm; IR (ATR): \(\overline{v}\) = 3303, 3106, 2958, 2871, 2191, 1680, 1658, 1616, 1512, 1429, 1359, 1249, 1215, 1141, 1041, 765 cm−1; MS: m/z (%) = 336 (M+, 100), 327 (32), 310 (24), 279 (60).