Delascar Camargoa,
Carlos Cifuentesa,
Juan-Carlos Castilloab and
Jaime Portilla*a
aBioorganic Compounds Research Group, Department of Chemistry, Universidad de Los Andes, Carrera 1 No. 18A-10, Bogotá 111711, Colombia. E-mail: jportill@uniandes.edu.co
bEscuela de Ciencias Químicas, Universidad Pedagógica y Tecnológica de Colombia, Avenida Central del Norte 39-115, Tunja, Colombia
First published on 15th July 2024
Despite the limited applications and scarcity of commercial examples of imidazo[1,2-a]pyrimidines, their exceptional properties hold great potential, representing a significant challenge in discovering more critical applications. Herein, we present a microwave-assisted approach for preparing 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones and their alkylation and bromination products using easily accessible and inexpensive reagents, thus offering a promising avenue for further search. Notably, the photophysical properties of an N-alkyl derivative were investigated, and the results highlight the high potential of these compounds as modular fluorophores. All the products were obtained with high yields using highly efficient protocols, and the regioselectivity of the reactions was determined on the basis of NMR measurements and X-ray diffraction analysis.
Fig. 1 Molecular structures of (a) some diazolopyrimidine derivatives and (b) relevant imidazo[1,2-a]pyrimidines-based compounds. |
Notably, the imidazo[1,2-a]pyrimidine (IP) motif has been found in molecules with antileishmanial,12 anticancer,13,14,17 antibacterial,15 and antiinflammatory16 activities, and various ways of synthesizing imidazo[1,2-a]pyrimidines (IPs) have been developed. However, in addition to articles9–17,22–31 and patents,32,33 only few specialized reviews18–21 on IPs are available. These compounds generally allow structural changes at positions 2, 3, or 5–8 via ring building or functionalization with aromatic substituents, redox, or metal-mediated C–C coupling reactions. IP ring construction is mostly achieved by cyclocondensation reactions of (i) 2-aminopyrimidines (amidine-type reagent) with 1,2-bis-electrophilic compounds (e.g., α-haloketones and α-alkoxy ketones) or (ii) 2-aminoimidazoles with 1,3-bis-electrophiles (β-diketones, β-alkoxyenones, etc.), of which the former route is the principal method (Scheme 1a).9–33
Most approaches for the synthesis of imidazo[1,2-a]pyrimidines have the typical operational difficulties (i.e., multistep synthetic procedures with low overall yields, poor availability or solubility of starting materials, tedious processes, long reaction times, and reactions mediated by expensive catalysts or additives).9–33 Therefore, developing efficient and alternative synthetic methods to obtain them from economic reagents using low energy is highly valuable. In this context, microwave (MW)-assisted synthesis is being intensively studied as these methods seem ideal and usually result in yields superior to conventional heating protocols.7,34–38 Indeed, many similar compounds are synthesized by our research group under microwave irradiation; for example, we obtained excellent results in the preparation of substituted imidazoles using amidines (1) (poorly soluble in organic solvents) and α-bromoacetophenones (2) (Scheme 1b).36–38
Although various commercial 2-aminopyrimidines are cheap, their poor solubility and high melting points limit their use in synthesis.39–41 For example, we could find only five reports on IP synthesis using 2-amino-6-methylpyrimidin-4(1H)-one (3, 6-methylisocytosine);14,15,42–44 particularly, 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones (4) were obtained with poor to good yields via the reaction of 3 (≥2 equiv.) with α-bromoketones 2 under reflux in DMF14,42–44 or ethanol (with NaHCO3 and 1 equiv. of 3).15 Remarkably, among the three recent works reporting crucial biological results,14,15,44 the best yield and more molecular diversity were reported in 2020 by Kawaguchi's group.14 This group also obtained the biologically active N-alkylated products (6) by reacting 4 (mainly from Ar = 4-ClPh) with alkyl halides (5) (2 equiv.) and an excess (4 equiv.) of cesium carbonate (Scheme 2a).14 In 1966, Pyl and Baufeld reported a method for obtaining an N-methyl-2-phenyl derivative (74% yield) using dimethyl sulfate (5 equiv.) and sodium hydroxide.29 Considering these findings and our interest in improving and standardizing synthetic methods under MW conditions,36–38,45 in this work, we used this technique to obtain 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones 4a–e and a new family of their N-alkylation products 6a–o (Scheme 2b). The 8-alkyl-2-arylimidazo[1,2-a]pyrimidinones 6a–o exhibited good solubility in organic solvents, meeting the desired expectations and incurring low cost as this approach involved cheap and easily accessible intermediates and reagents.
The reaction scope was examined using an equimolar mixture of 6-methylisocytosine (3) and α-bromoacetophenones 2a–e (1 mmol) under MW heating at 160 °C for 20 minutes. This reaction yielded 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones 4a–e with high yields as white-yellow solids that had high melting points (Scheme 4).
Notably, pure products were obtained when the reaction mixture was treated with water (3 mL), the deposited solid was collected by simple filtration, washed with cold ethanol (2 × 2 mL), and placed under a high vacuum for one hour at 60 °C. In addition, almost no loss of reaction efficacy was observed with the α-bromoketones tested, evidencing that the electronic nature of the substituent in the phenyl ring had little effect on the reactivity of 2a–e. However, the lowest yield was observed for 4e as the reaction mixture turned dark when the nitro-substituted substrate 2e was used, which may be due to its high polarity. These results suggest the feasibility of improving the synthetic method of 4a–e using sustainable protocols (i.e., ecological, social, and economic scopes) compared with other reported synthetic methods.
Entry | Solvent | Base | T (°C) | t (min) | Yield (%) |
---|---|---|---|---|---|
a Reactions conditions: 4a (0.25 mmol) and 5a/base (1 equiv.). Experiments performed in 10 mL sealed tubes under MW in 0.5 mL of the solvent. NR = no reaction.b 5a/base (2 equiv.).c 5a/base (1.5 equiv.). | |||||
1 | — | NaH | 150 | 15 | NR |
2 | tBuOK | NR | |||
3 | Na2CO3 | Traces | |||
4 | K2CO3 | 16 | |||
5 | MeCN | 33 | |||
6 | DMSO | Traces | |||
7 | DMF | 55 | |||
8b | K2CO3b | 70 | |||
9b | 130 | 75 | |||
10b | 100 | 83 | |||
11b | 60 | 43 | |||
12b | 60 | 77 | |||
13c | K2CO3c | 100 | 15 | 85 | |
14c | 60 | 80 | |||
15c | MeCN | 67 |
Subsequently, the substrate 5a and the potassium carbonate equivalents were doubled, the temperature was reduced, and the reaction time was increased (entries 8 to 12, Table 1); in these experiments, the best results were obtained when the reaction was carried at 100 °C for 15 minutes (entry 10). Ultimately, the equivalent amounts of the substrate and base were reduced to 1.5, which afforded the optimal results at 100 °C for 15 minutes in DMF as the solvent (entry 13). However, good results were obtained when the reaction was carried out at 60 °C for 1 hour and even in acetonitrile as the solvent at 100 °C (entries 12 and 15). Therefore, with the optimal conditions in hand to form 6a, we investigated the scope of the N-alkylation reaction for 4a–e using alkyl bromides 5a–c (Scheme 5). In general, the reaction showed excellent tolerance of reagents, resulting in the desired products 4a–o as colorless solids with outstanding yields (>73%). In addition, the conditions used for obtaining the precursors and products are better than those for reported IPs (i.e., 4a–e and 6b, 6g, and 6l).
Once the IPs 6a–o were obtained, the practical utility of this approach in medical and synthetic chemistry settings was explored. Specifically, the preparation of the anticancer agent ethyl 2-(4-chlorophenyl)-7-methyl-5-oxoimidazo[1,2-a]pyrimidine-8-acetate (6p) and the reactivity of the rings in 6a–e in the bromination reaction were evaluated (Scheme 6). Notably, Kawaguchi et al.14 have identified ester 6p (Hit A) as a potent and selective autotaxin (ATX) inhibitor that rescues the ATX-induced cardia bifida phenotype in zebrafish embryos. They obtained 6b and other N-alkyl derivatives by an approach similar to that used for 6a–o (see Scheme 2a); however, our standard MW-assisted approach proved more efficient in various aspects (Schemes 4–6a).
Furthermore, the reactivity of 6a–e was successfully evaluated by a simple bromination reaction. The imidazo[1,5-a]pyrimidine ring can react with electrophiles at two places, but the π-excessive nature of imidazole favors position 3 over 6 in the pyrimidine core. Most electrophilic aromatic substitution (EAS) reactions lead to 3-substituted products,18–21,43 but the alkyl group in 6a–e played a crucial role in their reactivity. Indeed, 3,6-dibrominated IPs 8a–e were easily obtained, while directed regioselectivity could not be achieved despite strict control of the reaction conditions. For example, in the NMR and HRMS analyses of the reaction crude of 6b with 1 equiv. of bromine at 0 °C for 10 min, a mixture of compounds was observed (i.e., 8b > 6-Br6b > 3-Br6b > 6b), evidencing the high reactivity of 6b and its preference to form the dibrominated product 8b. As a result, by using 2 equiv. of bromine for 1 hour at room temperature, compounds 8a–e were efficiently obtained (Scheme 6b). This type of compound would be useful in Pd-catalyzed C–C cross-coupling reactions,18–21 and the reaction approach may spearhead future syntheses based on EAS reactions of the imidazo[1,2-a]pyrimidine ring.
The structures of the compounds obtained were elucidated by HRMS analysis and 1H and 13C NMR spectroscopy, including some two-dimensional methods (see experimental processes, characterization data, and NMR spectra in ESI†). Gratifyingly, recrystallization of the 3,6-dibromoimidazo[1,5-a]pyrimidine 8b from a chloroform–methanol mixture (1:1 v/v) afforded crystals of suitable size and quality for single-crystal X-ray diffraction analysis (Scheme 6b).49
On the other hand, we performed a preliminary photophysical study of the 2-(4-methoxyphenyl) derivative 6i to establish the scope of the imidazo[1,5-a]pyrimidine heterocyclic core as an organic fluorophore due to its limited exploration9–11 and our wide interest in this field (Fig. 2 and Table 2).7,8 This study was conducted to classify compounds 6a–o as strategic intermediates of novel functional fluorophores due to their high synthetic viability. In particular, 6i was chosen for the research since its aryl group (i.e., 4-MeOPh) has revealed exceptional photophysical results in a similar 5:6 heterocyclic core, namely the pyrazolo[1,5-a]pyrimidine ring, by intramolecular charge transfer (ICT) photophysical phenomena.9–11
Fig. 2 (a) UV-vis absorption and (b) fluorescence emission (normalized, λex = 315 nm) spectra of 6i in different solvents (6.6 μM) at 20 °C. The inset shows the photograph of 200 μM solutions. |
Solvent | λabs (nm) | ε (M−1 cm−1) | λem (nm) | SS (cm−1) | ϕF | B(ε × ϕF) |
---|---|---|---|---|---|---|
a Quantum yield (ϕF) values were determined using Prodan as the standard. Absorbance (ab), fluorescence emission (em), molar absorption coefficient (ε), Stokes shift (SS), and calculated brightness (B) data are shown. | ||||||
ACN | 281, 315 | 8540 | 412 | 7474 | 0.113 | 966 |
DMF | 282, 317 | 14094 | 420 | 7736 | 0.070 | 993 |
DCM | 283, 314 | 10054 | 404 | 7095 | 0.085 | 854 |
AcOEt | 279, 314 | 12578 | 414 | 7693 | 0.182 | 2286 |
TBME | 279, 314 | 8170 | 406 | 7217 | 0.087 | 713 |
CH | 281, 308 | 10505 | 420 | 8658 | 0.040 | 421 |
The UV-vis and fluorescence emission spectra of 6i were achieved in six solvents with different polarities, including cyclohexene (CH), t-butyl methyl ether (TBME), dichloromethane (DCM), ethyl acetate (AcOEt), N,N-dimethylformamide (DMF), and acetonitrile (MeCN); the results are shown in Fig. 2 and Table 2. Cyclohexene was used as the lowest polarity solvent since 6i is highly insoluble in alkanes (e.g., cyclohexane). The absorption spectra of 6i displayed two typical bands, one at 280 nm attributed to the π → π* transitions and the other at around 315 nm due to the attenuation So → ICT transitions (i.e., MeO → CO), which are attenuated by the dipolar nature of the fused ring of 6i. As a result, the polarity of the microenvironment moderately influenced the photophysical properties of 6i (Fig. 2a). Fluorophore 6i displayed large Stokes shifts (7474–8658 cm−1) without a specific solvatofluorochromic shift in the six evaluated solvents; however, 6i exhibited appreciable fluorescence intensity (ϕF of up to 0.18), and the highest fluorescence quantum yield (ϕF) and brightness (B = ε × ϕF = 2286) values were achieved in a medium-polarity solvent AcOEt (Fig. 2b and Table 2). From these results, we can establish that the heterocyclic core of imidazo[1,2-a]pyrimidine is a promising functional fluorophore for application in detection chemistry, diagnostic bioimaging, and photosensitizers.2,9–11
Footnote |
† Electronic supplementary information (ESI) available: NMR spectra and crystallographic details. CCDC 8d 2358854. For ESI and crystallographic data in CIF or other electronic format see DOI: https://doi.org/10.1039/d4ra03948c |
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