Iodine-Catalyzed Multicomponent Synthesis of Highly Fluorescent Pyrimidine-Linked Imidazopyridines.

Herein, we report a metal-free one-pot three-component reaction of aryl methyl ketones, 2-aminopyridines, and barbituric acids for the synthesis of pyrimidine-linked imidazopyridines using a catalytic amount of molecular iodine in DMSO medium. This process involves a one-pot C-H oxidation, followed by the formation of one C-C and two C-N bonds. A wide variety of aryl methyl ketones and 2-aminopyridines were found to be suitable for this methodology. The UV and fluorescence properties of the synthesized products were studied in water and DMSO media. Most of the synthesized products exhibited very good to excellent fluorescence quantum yield. Among all the products, compounds 4p and 4q showed the maximum fluorescence quantum yield (0.36) in water medium under basic conditions and compound 4c showed the maximum fluorescence quantum yield (0.75) in DMSO medium.

Introduction

Imidazopyridine is a privileged scaffold found in many natural products as well as in synthetic pharmaceuticals.[1] Imidazopyridine-containing molecules exhibit a wide range of bioactivities such as anticancer,[2] antiparasitic,[3] antiviral, antibacterial, and anti-inflammatory activities, and they are PD-L1 antagonists[4] as well as a suppressor of tumors.[5] Prescription medicines such as zolpidem, zolimidine, nicopidem, saripidem, and olprinone have an imidazopyridine core.[1a] Recently, many functionalized imidazopyridine derivatives have been reported in the literature using metal and photocatalyzed C–H activation processes.[6] In addition to its pharmaceutical importance, the imidazopyridine moiety has gained considerable attention due to its fluorescence and chemosensing properties.[7a−7e] Considering the enormous applications of imidazopyridines over the years, several synthetic methods have been reported using metal-catalyzed,[8] metal-free,[9] electrochemical,[10] and light-induced[11] reaction conditions employing either two or multicomponent reactions (MCRs).

Similar to imidazopyridines, the pyrimidine moiety, especially barbituric acid and its derivatives, is an important pharmacophore and exhibits diverse medicinal properties.[12] The design and synthesis of hybrid molecules bearing more than one pharmacophore has gained considerable interest in recent times.[13] Considering the importance of hybrid molecules, imidazopyridines and the pyrimidine moiety, and in continuation of our work on the development of new methodologies,[14] we turned our attention to developing a new metal-free methodology for the synthesis of pyrimidine-linked imidazopyridines from the readily available starting materials. From the literature, we realized that the reaction of aryl methyl ketone and aminopyridine has been utilized for the preparation of diverse substituted imidazopyridine derivatives under different reaction conditions (Scheme ). Wu et al. reported the reaction of aryl methyl ketone and 2-aminopyridines in the presence of a stoichiometric amount (1.5 equiv) of iodine in DMSO medium for the preparation of 2-aryl-3-(pyridine-2-ylamino)imidazo[1,2-a]pyridines (Scheme , eq a).[15] Zeng et al. demonstrated the synthesis of chloroimidazo[1,2-a]pyridines from the reactions of aryl methyl ketones, 2-aminopyridine, and SOCl2 in the presence of H2SO4 in CHCl3 medium (Scheme , eq b).[16] Iida et al. developed a three-component reaction for the synthesis of thioether-linked imidazopyridines using the dual catalysis of flavin and iodine as shown in Scheme , eq c.[17] Very recently, Ma et al. have reported a one-pot three-component reaction for the synthesis of 3-arylimidazopyridines employing iodine catalysis and DMSO as the one-carbon source (Scheme , eq d).[18] In this paper, we report an iodine-catalyzed three-component reaction in DMSO medium for the synthesis of pyrimidine-linked imidazopyridine hybrids and study their photophysical properties (Scheme , eq e). Previously, we reported iodine–DMSO-mediated synthesis of 2-arylbenzo[d]imidazo[2,1-b]thiazole derivatives[14d] using a stoichiometric amount of iodine. Interestingly, we found that this reaction provides better results in the presence of a catalytic amount of iodine in DMSO medium. DMSO plays dual role as a solvent as well as an oxidant in this reaction.

Scheme 1

Comparison of the Present Work with Some Reported Methods

Results and Discussion

We initiated the present study by taking 4′-methoxyacetophenone (1d), 1,3-dimethylbarbituric acid (2a), and 2-aminopyridine (3a) as the model substrates. The initial reaction was tried on a 0.5 mmol scale using a 1:1:1 ratio of 1d, 2a, and 3a in the presence of 1.5 equivalent of molecular iodine in 3.0 mL DMSO, and the mixture was kept at 110 °C for 6 h. Interestingly, in this attempt, the corresponding three-component product 4d was obtained in 50% yield only. The product 4d was fully characterized by recording the 1H, 13C NMR, as well as HRMS spectra. With this encouraging result in hand, we turned our attention to optimize the reaction conditions. For optimization, we performed the reaction at different temperatures keeping 150 mol % of molecular iodine in DMSO medium (Table , entries 2–4). From these reactions, we realized performing this reaction below 100 °C provided lower yields, and increasing the temperature above 110 °C provided no benefit in terms of the reaction time or yield. As a result, we decided to try all the other reactions at 110 °C. Replacing DMSO by other solvents such as DMF, acetonitrile, ethanol, water, and toluene did not provide the desired product 4d (Table , entries 5–9). Thus, DMSO was considered as an essential solvent cum oxidizing agent for this three-component reaction.

Table 1

Optimization of the Reaction Conditionsa

entry	solvent	iodine source (mol %)	reaction temperature (°C)	4d, yield (%)b
1	DMSO	I2 (150 mol %)	110	50
2	DMSO	I2 (150 mol %)	130	50
3	DMSO	I2 (150 mol %)	150	50
4	DMSO	I2 (150 mol %)	90	45
5	DMF	I2 (150 mol %)	110	0
6	acetonitrile	I2 (150 mol %)	110	0
7	EtOH	I2 (150 mol %)	110	0
8	H2O	I2 (150 mol %)	110	0
9	toluene	I2 (150 mol %)	110	0
10	DMSO	I2 (200 mol %)	110	25
11	DMSO	I2 (100 mol %)	110	60
12	DMSO	I2 (50 mol %)	110	66
13	DMSO	I2 (30 mol %)	110	72
14	DMSO	I2 (20 mol %)	110	78
15	DMSO	I2(10 mol %)	110	85
16	DMSO	I2 (5 mol %)	110	40c
17	DMSO	NaI (100 mol %)	110	trace
18	DMSO	KI (100 mol %)	110	trace
19	DMSO	TBAI (100 mol %)	110	trace

Reaction conditions: 1d (0.5 mmol), 2a (0.5 mmol), and 3a (0.5 mmol) in 3.0 mL solvent, and the reaction was performed for 6–8 h.

Isolated Yield.

Reaction was performed for 24 h.

After this, we turned our attention to optimize the amount of iodine. Interestingly, the model reaction in the presence of 200 mol% of iodine in DMSO medium provided only 25% yield (Table , entry 10). Thus, we started the screening of the model reactions using 100, 50, 30, 20, and 10 mol % of iodine in DMSO medium, and the results are summarized in Table , entries 11–15. It is noteworthy to mention that we observed better yields on lowering the iodine stoichiometry. Further decreasing the amount of iodine took a very long time (24 h), and very less yield was observed (Table , entry 16). We have also tried other iodine sources such as NaI, KI, and TBAI; however, in all these cases, only trace amounts of the desired product were found (Table , entries 17–19). Thus, 10 mol % of molecular iodine in DMSO medium and 110 °C were considered as the optimized reaction conditions for this transformation.

With these optimized conditions, we next explored the generality and scope of this three-component reaction by taking several electron-donating and -withdrawing substituents on the aromatic ring of acetophenone and 2-aminopyridine derivatives. This MCR was found to be compatible with a wide range of acetophenone derivatives, and the results are summarized in Table . For this MCR, acetophenone derivatives with electron-donating substituents such as −Me, −Et, −OMe, and −methylenedioxy and electron-withdrawing groups such as −Cl, 3,4-diCl, −Br, −CF3, and −NO2 were found to be suitable. The reaction proceeded well, even with the bulky aryl methyl ketones such as naphthyl, fluorene, and biphenyl. Aryl methyl ketones having electron-withdrawing substituents provided relatively lesser yields than the ketones having electron-donating groups. We also varied 2-aminopyridine, and, in all the cases, we observed good to very good yields. Similar to 1,3-dimethylbarbituric acid, barbituric acid was also found to be suitable for this three-component reaction and the corresponding three-component product 4u was obtained in 69% yield under the standard reaction conditions. To further check whether the ortho-substituted acetophenone will give the similar result, we have reacted 2-chloro acetophenone and obtained the corresponding product 4v in 57% yield.

Table 2

Substrate Scope for the One-Pot Synthesis of Pyrimidine-Linked Imidazo[1,2-a]pyridinesa

Reaction conditions: compound 1 (0.5 mmol), molecular I2 (10 mol %), and DMSO (2.0 mL) were taken in a 10 mL round-bottom flask. The mixture was stirred until the disappearance of 1 (by TLC monitoring) keeping the reaction temperature at 110 °C. To this mixture, 2 (0.5 mmol) and 3 (0.5 mmol) were added and continued stirring until the completion of the reaction.

From the literature, we found that imidazopyridine derivatives exhibit interesting fluorescence properties.[7a−7e] We also found that most of our synthesized compounds are highly fluorescent under UV light, whereas some other compounds did not show any fluorescence. Thus, to study the electronic effect of substituents on the fluorescence property of our hybrid molecules having imidazopyridine and pyrimidine moieties, we then turned our focus toward their photophysical study. For the photophysical studies, first we prepared the sodium salt of our products by dissolving the product in 0.25 M NaOH aqueous solution. Under this basic condition, all the products were found to be highly soluble in water medium. Next, we studied photophysical properties of all the synthesized compounds in water medium. Initially, the UV–visible and steady-state fluorescence spectra of 4a having an unsubstituted phenyl ring and a 1,3-dimethylbarbituric acid moiety in 0.25 M NaOH solution in water medium were recorded.

The quantum yield of 4a was calculated using quinine sulfate dihydrate in 0.1 M H2SO4 (Φstd = 0.54) as the fluorescence standard. The calculated quantum yield (Φ) of 4a was found to be 0.33. Then, quantum yield of compound 4d having the 4-OMe substituent was recorded, in this case the quantum yield increased to 0.336, whereas for compound 4k having the 4-NO2 substituent, the fluorescent property vanished (Φ = 0). A comparative plot of the UV and fluorescence spectra of 4a, 4d, and 4k is shown in Figure a,b. Interestingly, the compound having both −NO2 and −OMe groups on the phenyl ring (4l) also did not show any fluorescence property (Φ = 0). Next, using similar methods, photophysical data of all the synthesized products was recorded, and the results are summarized in Table . Among all the screened compounds, compounds 4p and 4q showed the maximum fluorescence quantum yield.

Figure 1

(a) UV spectra of 4a, 4d, and 4k. (b) Fluorescence spectra of 4a, 4d, and 4k.

Table 3

Photophysical Data of Compounds 4a–4u in Water Medium under Basic Conditionsa

S. no.	compound	λabs(max) (nm)	abs.	λex (nm)	λem(max) (nm)	Stokes shift (nm)	quantum yield (Φ)
1	4a	323	0.203	323	436	113	0.330
2	4b	323	0.133	323	438	115	0.309
3	4c	324	0.261	324	434	110	0.308
4	4d	325	0.250	325	435	110	0.336
5	4e	325	0.153	325	430	105	0.290
6	4f	323	0.149	323	435	112	0.311
7	4g	325	0.129	325	434	109	0.172
8	4h	325	0.268	325	438	113	0.005
9	4i	325	0.266	325	432	107	0.007
10	4j	324	0.13	324	434	110	0.138
11	4k	306	0.355	306	439	133	0.005
12	4l	323	0.254	323
13	4m	325	0.275	325	476	151	0.057
14	4n	331	0.482	331	441	110	0.231
15	4o	328	0.421	328	474	146	0.150
16	4p	322	0.156	322	440	118	0.360
17	4q	324	0.246	324	434	110	0.360
18	4r	336	0.100	336	460	124	0.170
19	4s	335	0.181	335
20	4t	334	0.112	334
21	4u	327	0.21	327	467	140	0.125
22	4v	316	0.065	316	438	122	0.05

All spectra were recorded in 0.25 M NaOH solution with the compound concentration c = 3 × 10–5 M at room temperature.

Next, we tried to check the photophysical properties of these pyrimidine-linked imidazo[1,2-a] pyridines in organic solvents. For that, the UV and steady-state fluorescence spectra of compound 4q were recorded in various organic solvents such as DMSO, DMF, acetonitrile, chloroform, and ethanol (Figure a,b). Interestingly, in organic solvents, a drastic increase of quantum yield for 4q was observed. In DMSO medium, 4q showed the maximum quantum yield (Φ = 0.69), followed by in DMF (Φ = 0.51), in EtOH (Φ = 0.43), and in acetonitrile (Φ = 0.41), but in CHCl3 the value decreased drastically (Φ = 0.18).

Figure 2

(a) UV spectra of compound 4q in different solvents. (b) Fluorescence spectra of compound 4q in different solvents.

As we observed the highest fluorescence quantum yield of 4q in DMSO medium, we turned our attention to study the UV and fluorescence properties of remaining all the products in the same organic medium, and the results are summarized in Table .

Table 4

Photophysical Data of 4a–4u and 5 in DMSO Mediuma

sample code	λmax (nm)	abs.	λex (nm)	λem (nm)	Stokes shift (nm)	quantum yield (Φ)
QS	346	0.098	346	449	103	0.546
4a	345	0.06	345	456	111	0.610
4b	346	0.052	346	455	109	0.571
4c	346	0.036	346	456	110	0.750
4d	346	0.088	346	453	107	0.614
4e	346	0.037	346	449	103	0.605
4f	346	0.03	346	455	109	0.591
4g	347	0.042	347	457	110	0.460
4h	355	0.143	355
4i	346	0.012	346
4j	350	0.036	350	457	107	0.651
4k	410	0.031	410
4l	346	0.028	346
4m	355	0.166	355	483	128	0.567
4n	356	0.157	356	466	110	0.448
4o	353	0.112	353	486	133	0.631
4p	346	0.042	346	455	109	0.663
4q	346	0.071	346	450	104	0.692
4r	360	0.041	360	481	121	0.200
4s	365	0.01	365
4t	355	0.015	355
4u	346	0.063	346	458	112	0.567
4v	340	0.024	340	457	117	0.16
5	317	0.08	317	379	62	0.48

All spectra were recorded in DMSO with concentration c = 3 × 10–5 M at room temperature.

Compound 4a initially showed Φ = 0.33 in water under basic conditions, whereas in DMSO medium it increased to Φ = 0.61. Likewise, 4b, 4c, 4d, 4e, and 4f having electron-donating substituents on the phenyl ring showed a significant increase in quantum yields with Φ = 0.57, 0.75, 0.614, 0.60, and 0.69, respectively, in DMSO medium. Compound 4g having the 4-Cl substituent on the phenyl ring showed quantum yield Φ = 0.46 in DMSO medium. Similar to water medium, in DMSO also 4h and 4i did not exhibit fluorescence properties. Interestingly, 4j having the −CF3 substituent on the phenyl ring showed Φ = 0.651 in DMSO medium.

Like in water medium, in DMSO also, compounds 4k and 4l, which contain a −NO2 group on the phenyl ring, did not show fluorescence. Our observation is also in agreement with the literature reports, which state that the introduction of a −NO2 group to the fluorophore quenches the overall fluorescence intensity due to three factors: (i) it favors intersystem crossing leading to efficient triplet formation,[19] (ii) helps in the formation of dark charge transfer states for non-radiative decay to the ground state,[20] and (iii) provides non-radiative pathways for efficient internal conversion.[21] Compound 4m that has a naphthyl ring showed around 11 times higher quantum yield Φ = 0.56 in DMSO than in water medium. Likewise, imidazopyridines 4n and 4o having fluorenyl and biphenyl rings showed very good quantum yields Φ = 0.44 and 0.63, respectively, in DMSO medium. Compound 4u that contains the unsubstituted barbituric acid moiety also showed a significant quantum yield (Φ = 0.56). Compound 4v showed quantum yield Φ = 0.05 in basic solution of water and Φ = 0.16 in DMSO medium. In Figure , we have shown a picture of some highly fluorescent products in DMSO medium under UV light. Considering the high fluorescence intensity of most of the synthesized products, both in organic and aqueous media, it is expected that these molecules may find applications in chemosensing.

Figure 3

Photograph of some of the highly fluorescent compounds in DMSO medium under UV light.

To further compare and check the effect of the barbituric acid moiety on fluorescence property, we have prepared the 2-phenylimidazo[1,2-a]pyridine 5 from the reaction of 2-aminopyridine 2a and 2-bromoacetophenone and recorded the UV and fluorescence spectra in DMSO by considering quinine sulfate dihydrate as the fluorescence standard. Interestingly, we have observed 0.48 as the quantum yield of 5, while the quantum yield (Φ) of 4a, initially recorded in DMSO, was Φ = 0.61 (Figure ). The Stokes shift of 5 is 62 nm, while it is 111 nm for compound 4a that contains the 1, 3-dimethylbarbituric acid moiety (the UV and fluorescence spectra of 5 are available in the Supporting Information). From this study, we confirmed that the incorporation of the barbituric acid moiety increases the fluorescence property of imidazopyridine.

Figure 4

Comparison of quantum yields of 5 and 4a.

Finally, based on our research findings and literature reports, we have proposed a plausible reaction pathway for the iodine-catalyzed three-component synthesis of 4 in Scheme . It is believed that initially, acetophenone derivative 1 reacts with iodine to produce intermediate [A] and byproduct HI. This HI in the presence of DMSO regenerates I2 for the next cycle. After this, in the presence of DMSO, A transforms into the corresponding phenylglyoxal B, which upon reaction with 2by Knoevenagel condensation provides C. The aza-Michael attack of 3 on C provides intermediate D, which upon cyclization provides E, which after loss of H2O gives desired product 4.

Scheme 2

Proposed Reaction Pathway for the Formation of Iodine-Catalyzed Pyrimidine-Linked Imidazopyridines

Conclusions

In summary, we have developed a metal-free one-pot methodology for the synthesis of pyrimidine-linked imidazopyridines using iodine catalysis in DMSO medium. This reaction involves a one-pot C–H oxidation, followed by the formation of three new bonds (one C–C and two C–N). The salient features of this methodology are a wide substrate scope, good to very good yields, no need of column chromatographic purification, and the presence of more than one bioactive moieties in the products. In addition to these, we have found that most of the synthesized products exhibit very good to excellent fluorescence quantum yields. We have carried out the photophysical studies of all the products in aqueous medium under basic conditions as well as in DMSO medium.

Experimental Section

General Information

All the starting materials were purchased from commercial sources (Sigma-Aldrich, Merck, and Alfa-Aesar) and used as such without further purification. Reactions were monitored by TLC. Melting points were determined using an SRS EZ-Melt automated melting point apparatus by capillary methods and uncorrected. The NMR spectra were recorded using Bruker 400 MHz and JEOL 500 MHz spectrometers in DMSO-d6 with tetramethyl silane as the internal standard or adding NaOH in D2O. Chemical shift values are reported in δ values (ppm) downfield from tetramethyl silane. HRMS analysis was carried out using a Bruker Impact HD mass spectrometer (Impact HD UHRTOF, ESI with the positive mode) mass spectrometer.

Experimental Procedure

In a 10.0 mL round-bottom flask fitted with a reflux condenser, 0.5 mmol of acetophenone derivative (1), 10 mol % of I2 (12.69 mg), and 2.0 mL of DMSO were added, and the solution was kept under heating at 110 °C with constant stirring until the reactant 1 was totally consumed (monitored by TLC). Then, barbituric acid derivative (2) (0.5 mmol) was added to the mixture and stirred for 5 min. Subsequently, 2-aminopyridine (3) (0.5 mmol) was added to the flask, and the mixture was kept at the same temperature with constant stirring. After the completion of the reaction, the reaction mixture was cooled to room temperature, 10 mol % sodium thiosulfate solution (10.0 mL) was added, the solid mass was filtered off, and it was washed with hot ethyl acetate to get the pure three-component product 4.

6-Hydroxy-1,3-dimethyl-5-(2-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4a)[9b,9d]

White solid; 136 mg (78%); mp above 400 °C. 1H NMR (400 MHz, DMSO-d6): δ 8.30 (d, J = 4.0 Hz, 1H), 7.92 (t, J = 8.0 Hz, 1H), 7.88 (d, J = 8.0 Hz, 1H), 7.81 (d, J = 8.0 Hz, 2H), 7.49 (t, J = 8.0 Hz, 2H), 7.44–7.39 (m, 2H), 3.14 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6): δ 161.9, 153.1, 144.3, 138.4, 132.8, 131.8, 129.3, 128.9, 128.3, 127.8, 127.3, 121.8, 116.2, 111.5, 72.5, 27.2 ppm. HRMS (ESI-TOF) m/z: calcd for C19H17N4O3 [M + H]+, 349.1296; found, 349.1314.

6-Hydroxy-1,3-dimethyl-5-(2-(p-tolyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4b)[9b]

Light yellow solid; 147 mg (80%); charred at 375 °C. 1H NMR (400 MHz, saturated solution of NaOH in D2O): δ 7.88 (d, J = 4.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.57 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 7.25 (d, J = 8.0 Hz, 2H), 6.92 (t, J = 8.0 Hz, 1H), 3.26 (s, 6H), 2.32 (s, 3H) ppm. 13C{1H} NMR (100 MHz, saturated solution of NaOH in D2O): δ 168.4, 164.8, 154.6, 145.2, 142.2, 138.2, 131.2, 129.3, 126.8, 126.5, 124.6, 115.4, 112.7, 80.1, 27.9, 20.2 ppm. HRMS (ESI-TOF) m/z: calcd for C20H19N4O3 [M + H]+, 363.1452; found, 363.1454.

5-(2-(4-Ethylphenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4 (1H,3H)-dione (4c)

Light orange solid; 152 mg (81%); charred at 293–295 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.71 (d, J = 4.0 Hz, 1H), 7.64 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.21 (t, J = 8.0 Hz, 1H), 7.13 (d, J = 8.0 Hz, 2H), 6.78 (t, J = 8.0 Hz, 1H), 3.11 (s, 6H), 2.54–2.52 (m, 2H), 1.09 (t, J = 8.0 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 164.5, 161.6, 155.2, 145.2, 144.5, 142.9, 133.4, 129.1, 128.3, 126.6, 126.0, 118.4, 116.8, 114.8, 113.2, 79.2, 29.2, 29.0, 16.6 ppm. HRMS (ESI-TOF): m/z: [M + H]+ calcd for C21H21N4O3, 377.1608; found, 377.1634.

6-Hydroxy-5-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4d)

White solid; 161 mg (85%); charred at 384 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.74 (d, J = 8.0 Hz, 2H), 7.71 (d, J = 4.0 Hz, 1H) 7.49 (d, J = 12.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H), 6.87 (d, J = 8.0 Hz, 2H), 6.79–6.76 (m, 1H), 3.70 (s, 3H), 3.13 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.7, 159.2, 154.7, 144.6, 142.3, 129.3, 128.9, 125.8, 125.6, 118.3, 116.5, 114.6, 112.4, 78.1, 56.1, 28.6 ppm. HRMS (ESI-TOF) m/z: calcd for C20H19N4O4 [M + H]+, 379.1401; found, 379.1402.

6-Hydroxy-1,3-dimethyl-5-(2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4e)

Greenish white solid; 186 mg (85%); charred at 354 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.75 (d, J = 4.0 Hz, 1H), 7.50 (d, J = 12.0 Hz, 1H), 7.24–7.20 (m, 1H), 7.17 (s, 2H), 6.80 (t, J = 8.0 Hz, 1H), 3.68 (s, 6H), 3.62 (s, 3H), 3.11 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O) 163.9, 154.7, 153.4, 144.7, 142.2, 137.1, 131.8, 126.1, 119.2, 116.7, 112.8, 105.4, 78.2, 61.4, 56.5, 28.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C22H23N4O6, 439.1612; found, 439.1605.

6-Hydroxy-1,3-dimethyl-5-(2-(3,4,5-trimethoxyphenyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4f)

Light brown solid; 165 mg (84%); charred at 350 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.69 (d, J = 8.0 Hz, 1H), 7.47 (d, J = 8.0 Hz, 1H), 7.34 (dd, J = 8 Hz, 2 Hz, 1H), 7.28 (d, J = 4.0 Hz, 1H), 7.20 (t, J = 8.0 Hz, 1H) 6.84 (d, J = 8.0 Hz, 1H), 6.78 (t, J = 8.0 Hz, 1H), 5.90 (s, 2H), 3.11 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.7, 154.7, 147.9, 147.1, 144.6, 142.1, 130.4, 125.9, 121.9, 118.5, 116.6, 112.6, 109.3, 108.3, 101.8, 78.0, 28.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H17N4O5, 393.1193; found, 393.1189.

5-(2-(4-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4g)

Light yellow solid; 141 mg (74%); charred at 390–393 °C. 1H NMR (400 MHz, saturated solution of NaOH in D2O): δ 7.92–7.89 (m, 1H), 7.80–7.79 (m, 1H), 7.78–7.77 (m, 1H), 7.62–7.59 (m, 1H), 7.44–7.39 (m, 3H), 6.97–6.94 (m, 1H), 3.29 (s, 6H) ppm. 13C{1H} NMR (100 MHz, saturated solution of NaOH in D2O): δ 164.7, 154.6, 145.3, 141.2, 132.9, 132.7, 128.7, 128.2, 126.7, 124.8, 116.3, 115.5, 112.8, 79.9, 27.9 ppm. HRMS (ESI-TOF) m/z: calcd for C19H16ClN4O3 [M + H]+, 383.0905; found, 383.0890.

5-(2-(3,4-Dichlorophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4h)

White solid; 150 mg (72%); mp above 400 °C. 1H NMR (400 MHz, saturated solution of NaOH in D2O): δ 7.89 (d, J = 2.0 Hz, 1H), 7.86 (d, J = 8.0 Hz, 1H), 7.66 (dd, J = 8.0, 4.0 Hz, 1H), 7.57 (d, J = 12.0 Hz, 1H), 7.46 (d, J = 8.0 Hz, 1H), 7.38 (t, J = 8.0 Hz, 1H), 6.93–6.90 (m, 1H), 3.25 (s, 6H). 13C{1H} NMR (125 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 162.3, 153.8, 143.9, 138.9, 136.9, 131.1, 130.7, 129.2, 128.8, 127.3, 126.0, 125.1, 120.5, 116.5, 111.7, 76.3, 27.8 ppm. HRMS (ESI-TOF) m/z: calcd for C19H15Cl2N4O3 [M + H]+, 417.0516; found, 417.0499.

5-(2-(4-Bromophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4i)

Off-white solid; 149 mg (70%); mp above 400 °C. 1H NMR (400 MHz, saturated solution of NaOH in D2O): δ 7.91 (d, J = 4.0 Hz, 1H), 7.73 (d, J = 8.0 Hz, 2H), 7.62–7.56 (m, 3H), 7.41 (t, J = 8.0 Hz, 1H), 6.97–6.94 (m, 1H), 3.29 (s, 6H). 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 162.3, 153.8, 143.9, 140.5, 135.6, 131.3, 129.4, 125.8, 124.6, 120.1, 119.9, 116.4, 111.4, 76.4, 27.7. HRMS (ESI-TOF) m/z: calcd for C19H16BrN4O3 [M + H]+, 427.0400; found, 427.0407.

6-Hydroxy-1,3-dimethyl-5-(2-(3-(trifluoromethyl)phenyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4j)

Light yellow solid; 141 mg (68%); charred at 368 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 8.05 (s, 2H), 7.75 (d, J = 8.0 Hz, 1H), 7.53–7.50 (m, 3H), 7.26 (t, J = 8.0 Hz, 1H), 6.84–6.81 (m, 1H), 3.11 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 164.1, 154.9, 145.3, 140.9, 136.9, 131.7, 130.6, 130.3, 126.9, 126.9, 126.4, 124.68–124.60 (m), 124.17, 120.00, 117.09, 113.31, 78.51, 40.18, 39.96, 39.75, 39.52, 39.31, 39.09, 38.88, 28.82 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H16F3N4O6, 417.1169; found, 417.1173.

6-Hydroxy-1,3-dimethyl-5-(2-(4-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4k)

Yellow solid; 132 mg (67%); mp above 400 °C. 1H NMR (400 MHz, saturated solution of NaOH in D2O): δ 8.19 (d, J = 8.0 Hz, 2H), 7.99 (d, J = 12.0 Hz, 2H), 7.90 (d, J = 8.0 Hz, 1H), 7.59 (d, J = 8.0 Hz, 1H), 7.40 (t, J = 8.0 Hz, 1H), 6.96–6.93 (m, 1H), 3.29 (s, 6H) ppm. 13C{1H} NMR (100 MHz, D2O): δ 164.5, 154.5, 146.4, 145.5, 141.2, 139.9, 127.3, 127.2, 125.0, 123.9, 118.3, 115.8, 113.1, 79.7, 27.9 ppm. HRMS (ESI-TOF) m/z: calcd for C19H16N5O5 [M + H]+, 394.1146; found, 394.1136.

6-Hydroxy-5-(2-(4-methoxy-3-nitrophenyl)imidazo[1,2-a]pyridin-3-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4l)

Yellow solid; 151 mg (71%); charred at 320 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 8.24 (d, J = 2.4 Hz, 1H), 8.07 (dd, J = 8.8, 2.4 Hz, 1H), 7.73 (d, J = 8.0 Hz, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.29–7.22 (m, 2H), 6.81 (t, J = 8.0 Hz, 1H), 3.85 (s, 3H), 3.12 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.9, 154.7, 152.5, 145.0, 139.9, 139.6, 134.4, 128.8, 126.5, 126.3, 124.7, 119.4, 116.8, 115.3, 113.0, 78.2, 57.7, 28.7 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18N5O6, 424.1252; found, 424.1262.

6-Hydroxy-1,3-dimethyl-5-(2-(naphthalen-2-yl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4m)

White solid; 149 mg (75%); mp above 400 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 8.02 (s, 1H), 7.82–7.73 (m, 4H), 7.52 (t, J = 4.0 Hz, 2H) 7.34–7.31 (m, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.22 (d, J = 8.0 Hz, 1H) 6.82–6.79 (m, 1H), 3.13 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 164.0, 154.9, 145.1, 142.4, 134.1, 133.8, 133.2, 129.2, 128.64, 128.58, 127.4, 127.1, 126.7, 126.6, 126.3, 126.1, 119.7, 116.9, 112.9, 78.5, 28.8 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C23H19N4O3, 399.1452; found, 399.1441.

5-(2-(9H-Fluoren-3-yl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4n)

Off-white solid; 155 mg (71%); charred at 379 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 8.26 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.81–7.75 (m, 4H), 7.54 (d, J = 8.0 Hz, 1H), 7.46–7.40 (m, 2H), 7.25 (t, J = 8.0 Hz, 1H), 6.83–6.80 (m, 1H), 4.99 (s, 2H) 3.14 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.6, 154.6, 144.7, 144.1, 143.9, 142.6, 141.9, 140.8, 134.9, 127.9, 127.8, 126.9, 126.2, 125.9, 125.7, 124.8, 120.8, 120.5, 119.3, 116.6, 112.5, 78.1, 28.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C26H21N4O3, 437.1608; found, 437.1637.

5-(2-([1,1′-Biphenyl]-4-yl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4o)

Pale yellow solid; 165 mg (78%); charred at 396 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.90 (d, J = 8.0 Hz, 2H), 7.74 (d, J = 4.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 2H), 7.59 (d, J = 8.0 Hz, 2H), 7.52 (d, J = 8.0 Hz, 1H), 7.42 (t, J = 8.0 Hz, 2H), 7.30 (t, J = 8.0 Hz, 1H), 7.23 (t, J = 8.0 Hz, 1H) 6.82–6.79 (m, 1H), 3.13 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.7, 154.7, 144.8, 141.9, 140.7, 139.4, 135.4, 130.1, 128.55, 128.47, 127.3, 125.9, 119.4, 116.7, 112.6, 78.1, 28.6 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C25H21N4O3, 425.1608; found, 425.1602.

6-Hydroxy-1,3-dimethyl-5-(6-methyl-2-phenylimidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4p)[9b]

Light brown solid; 143 mg (79%); charred at 398 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.86 (d, J = 8.0 Hz, 2H), 7.51 (s, 1H), 7.42 (d, J = 12.0 Hz, 1H), 7.28 (t, J = 8.0 Hz, 2H), 7.17 (t, J = 8.0 Hz, 1H), 7.04 (d, J = 8.0 Hz, 1H), 3.12 (s, 6H), 2.23 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 162.7, 154.0, 143.0, 141.7, 136.4, 128.5, 127.5, 127.4, 126.9, 123.0, 120.6, 119.2, 115.9, 76.8, 27.9, 18.3 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H19N4O3, 363.1452; found, 363.1448.

6-Hydroxy-5-(2-(4-methoxyphenyl)-6-methylimidazo[1,2-a]pyridin-3-yl)-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4q)

Light pink solid; 165 mg (84%); charred at 375 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.76 (d, J = 8.0 Hz, 2H), 7.49 (s, 1H), 7.39 (d, J = 8.0 Hz, 1H), 7.04 (d, J = 12.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 3.72 (s, 3H), 3.11 (s, 6H), 2.21 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.3, 158.9, 154.4, 143.4, 142.0, 129.0, 128.9, 127.9, 123.1, 121.2, 118.1, 115.9, 114.3, 77.7, 55.8, 28.3, 18.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C21H21N4O4, 393.1557; found, 393.1585.

5-(7-Chloro-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4r)

White solid; 167 mg (81%); mp above 400 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.77 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 4.0 Hz, 1H), 7.58 (s, 1H), 6.88 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 4.0 Hz, 1H), 3.72 (s, 3H), 3.11 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.1, 159.2, 154.3, 143.8, 142.9, 130.0, 129.1, 128.3, 126.8, 118.9, 114.9, 114.4, 112.9, 77.1, 55.8, 28.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18ClN4O4, 413.1011; found, 413.1009.

5-(6-Bromo-2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4s)

Brown solid; 183 mg (80%); charred at 392–394 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.84 (s, 1H), 7.77 (d, J = 8.0 Hz, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 6.88 (d, J = 8.0 Hz, 2H), 3.72 (s, 3H), 3.11 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 163.6, 159.4, 154.6, 143.3, 143.0, 129.4, 128.3, 128.1, 119.0, 118.9, 117.7, 114.7, 106.3, 77.6, 56.0, 28.5 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H18BrN4O4, 457.0506; found, 457.0515.

5-(8-Chloro-2-phenyl-6-(trifluoromethyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4t)

Light green solid; 160 mg (71%); charred at 365 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 8.09 (s, 1H), 7.70 (d, J = 8.0 Hz, 2H), 7.59 (s, 1H), 7.31–7.28 (m, 2H), 7.25–7.22 (m, 1H), 3.08 (s, 6H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 164.9, 155.4, 146.1, 142.7, 134.9, 129.9, 129.6, 128.8, 125.9, 123.5, 123.2, 122.44–122.36 (m), 121.1, 116.3, 79.0, 29.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C20H15ClF3N4O3, 451.0779; found, 451.0784.

6-Hydroxy-5-(2-(4-methoxyphenyl)imidazo[1,2-a]pyridin-3-yl)pyrimidine-2,4(1H,3H)-dione (4u)[9d]

Light yellow solid; 121 mg (69%); charred at 366 °C. 1H NMR (400 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 7.79 (d, J = 8.0 Hz, 2H), 7.65 (d, J = 8.0 Hz, 1H), 7.43 (d, J = 8.0 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 6.86 (d, J = 8.0 Hz, 2H), 6.76–6.73 (m, 1H), 4.98 (s, 2H), 3.70 (s, 3H) ppm. 13C{1H} NMR (100 MHz, DMSO-d6 + saturated solution of NaOH in D2O): δ 172.3, 162.0, 159.1, 144.7, 141.7, 129.6, 129.3, 126.1, 125.4, 120.1, 116.4, 114.6, 112.2, 79.9, 56.2 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C18H15N4O4, 351.1088; found, 351.1100.

5-(2-(2-Chlorophenyl)imidazo[1,2-a]pyridin-3-yl)-6-hydroxy-1,3-dimethylpyrimidine-2,4(1H,3H)-dione (4v)

White solid; 139 mg (57%); charred at 364–366 °C. 1H NMR (400 MHz, DMSO-d6): δ 14.51 (s, 1H), 8.30 (d, J = 4.0 Hz, 1H), 7.95 (d, J = 8.0 Hz, 2H), 7.72 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 8.0 Hz, 1H), 7.52–7.49 (m, 1H), 7.44 (t, J = 8.0 Hz, 2H), 3.06 (s, 6H) ppm. 13C{1H} NMR (125 MHz, DMSO-d6): δ 161.7, 153.0, 138.1, 132.8, 132.6, 132.3, 131.4, 129.9, 129.9, 128.2, 127.7, 127.4, 123.9, 116.1, 111.6, 72.0, 27.1 ppm. HRMS (ESI-TOF) m/z: [M + H]+ calcd for C19H16ClN4O3, 383.0905; found, 383.0904.