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. 2025 Dec 22;28(1):157–162. doi: 10.1021/acs.orglett.5c04435

Access to Pyrazolo[1,5‑a]pyrimidinone Regioisomers from Acylated Meldrum’s Acids

Maxime Donzel 1,*, Erik Chorell 1,*
PMCID: PMC12797321  PMID: 41427767

Abstract

Two complementary and efficient methods for the regioselective synthesis of functionalized pyrazolo­[1,5-a]­pyrimidinones were developed from 3-aminopyrazoles and acylated Meldrum’s acids. Fine-tuning the reaction conditions enables selective access to either pyrazolo­[1,5-a]­pyrimidin-5-ones or -7-ones in high yields. This protocol offers a reliable route to pyrazolo­[1,5-a]­pyrimidin-5-ones, a subclass with few reported syntheses, and highlights the value of acylated Meldrum’s acids as building blocks for regioselective heterocycle synthesis and biologically relevant scaffold generation.

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The pyrazolo­[1,5-a]­pyrimidine (PP) scaffold has attracted a considerable amount of interest in recent years, with numerous reports on both its synthetic accessibility and its medicinal chemistry applications. This scaffold is found in approved drugs, such as zaleplon, and in drug candidates targeting cancer, diabetes, and microbial, viral, or parasitic infections. Reflecting this biological relevance, diverse synthetic strategies have been reported to access and selectively functionalize PPs. Within this family, two regioisomeric subclasses can be distinguished: pyrazolo­[1,5-a]­pyrimidin-7­(4H)-ones (PP-7-Os) and pyrazolo­[1,5-a]­pyrimidin-5­(4H)-ones (PP-5-Os) (Figure A). The PP-7-O scaffold is well-established, with numerous syntheses reported over the past several decades. The most common method involves condensing 3-aminopyrazoles with β-ketoesters to afford substituted PP-7-Os in good yields (Figure B). First described in 1981, this reaction is typically performed in boiling acetic acid, which serves as both the solvent and the acid catalyst. PP-7-Os have been reported with multiple applications in the field of medicinal chemistry as potential anticancer, antibacterial, or antidiabetic agents. In contrast, PP-5-Os remain underexplored, with few synthetic reports. The regioselective synthesis of an unsubstituted PP-5-O was described in 2007 from 3-aminopyrazole and 1,3-dimethyluracil. Previously, Remmingler had reported a similar cyclocondensation with ethyl phenylpropiolate, though in low yield and with limited data. Arbabri later improved this approach using activated alkynes, giving phenyl- and methyl-substituted PP-5-Os, and extended it to 7-trifluoromethyl derivatives. A related two-pot Sonogashira/cyclocondensation route to 7-heteroaryl-PP-5-Os was also developed, albeit with low yields (Figure C). These challenges have limited access to PP-5-Os, though their frequent appearance in patents underscores their pharmaceutical potential.

1.

1

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(A) Pyrazolo­[1,5-a]­pyrimidine core structures. (B) PP-7-O synthesis. (C) PP-5-O synthesis. (D) This work.

Herein, we report two straightforward and high-yielding one-pot synthetic routes that enable the regioselective access to both 5-substituted pyrazolo­[1,5-a]­pyrimidin-7­(4H)-ones (PP-7-Os) and 7-substituted pyrazolo­[1,5-a]­pyrimidin-5­(4H)-ones (PP-5-Os) from the same 3-aminopyrazole/acylated Meldrum’s acid building blocks (Figure D).

In our attempt to access isomers of both PP-5-Os and PP-7-Os, we identified acylated Meldrum’s acids as ideal starting materials. PP-7-Os are typically obtained by cyclocondensation of 3-aminopyrazoles with β-ketoesters, but the limited commercial availability of these intermediates often requires an in-house synthesis. In contrast, acylated Meldrum’s acids are readily prepared in one step and thermally decompose in ethanol through transient ketene intermediate I to release β-ketoesters. We therefore envisioned a one-pot process in which the β-ketoester, generated in situ, would react with 3-aminopyrazole to afford the desired PP-7-O 3 (Scheme , path A). In a non-nucleophilic solvent, we anticipated that reactive ketene intermediate I would form upon heating, as previously demonstrated, and react with the 3-aminopyrazole to give intermediate 4. Previous studies have reported amine, amide, and 3-aminopyrazole additions to ketenes generated from acylated Meldrum’s acids. One similar intermediate was shown to undergo intramolecular cyclization under acidic conditions. However, in that case, it was synthesized through several successive steps. We envisioned generating this intermediate directly from acylated Meldrum’s acid 2, enabling intracyclization to substituted PP-5-Os 5 (Scheme , path B). Unknown to us at the start of this project, a related patent described a similar concept, but it lacked experimental details and scope exploration and required a two-pot sequence, prompting us to investigate and optimize the process.

1. Synthetic Pathways to PP-5-Os and PP-7-Os.

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We first investigated the possibility of forming the β-ketoester intermediate from acylated Meldrum’s acid 2a (1.5 equiv), followed by direct cyclization with aminopyrazole 1a to obtain target PP-7-O regioisomer 3a. When both starting materials were stirred in ethanol for 16 h at 80 °C in a sealed tube, less than 10% conversion to 3a was observed, along with unreacted 1a and the expected β-ketoester intermediate (Table , entry 1). As β-ketoester condensation with aminopyrazoles has often been performed in acetic acid at high temperatures, 10 equiv of acetic acid was added. This resulted in the formation of regioisomer 3a in 52% yield; however, full consumption of 1 was not achieved (Table , entry 2). Replacing acetic acid with only 1 equiv of TFA improved the reaction, affording 3a in 86% yield, and simultaneously reduced the amount of 2a to only 1.2 equiv (Table , entry 3).

1. Optimization of the Reaction Conditions.

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entry 2 (equiv) conditions 3:4:5 ratio yield (3/4/5) (%)
1 2a, 1.5 EtOH (80 °C, 16 h) 1:0:0 <10/–/–
2 2a, 1.5 EtOH, AcOH (10 equiv, 80 °C, 16 h) 1:0:0 55/–/–
3 2a, 1.2 EtOH, TFA (1 equiv, 80 °C, 16 h) 1:0:0 85/–/–
4 2a, 1.5 DCE, TFA (5 equiv, 80 °C, 16 h) 19:0:81 nd/–/63
5 2a, 1.5 MeCN (80 °C, 16 h) 0:62:38 –/46/35
6 2a, 1.5 (i) MeCN (80 °C, 1 h) 0:0:1 –/–/86
(ii) TFA (1 equiv, 80 °C, 16 h)
7 2b, 1.5 (i) MeCN (80 °C, 1 h) 0:65:35 –/50/12
(ii) TFA (1 equiv, 80 °C, 16 h)
8 2b, 1.5 (i) MeCN (80 °C, 1 h) 0:0:1 –/–/75
(ii) p-TsOH (1.5 equiv, 80 °C, 16 h)
9 2a, 1.5 EtOH, p-TsOH (1 equiv, 80 °C, 16 h) 1:0:0 91/–/–
10 2a, 1.5 (i) MeCN (80 °C, 1 h) 0:0:1 –/–/94
(ii) p-TsOH (1 equiv, 80 °C, 16 h)
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a

Reaction conditions: aminopyrazole 1 (0.25 mmol), acylated Meldrum’s acid 2 (1.2–1.5 equiv), acid (0–10 equiv), solvent (1 mL, 0.25 M), 80 °C, sealed tube, indicated time. For two-step reactions, the acid was added directly to the reaction mixture.

b

Ratio from crude 1H NMR.

c

Isolated yield.

d

Not determined.

In parallel, we examined the conditions to selectively form PP-5-O regioisomer 5a. Initial attempts started by combining the reagents in dichloroethane with TFA and gave a mixture of regioisomers in a 2:8 ratio, in favor of 5a, with a 63% isolated yield (Table , entry 4). When the acid was added at the beginning of the reaction, complete regioselectivity in favor of 5a over 3a was never achieved. In acetonitrile, without acid, 4a and 5a were obtained exclusively, with no 3a detected, but conversion of 4a to 5a remained incomplete after 16 h at 80 °C (Table , entry 5). These results prompted us to adopt a stepwise strategy to ensure full conversion and preserve complete regioselectivity. First, 1a and 2a were reacted in acetonitrile for 1 h at 80 °C, and then, upon formation of 4a and full consumption of 1a, TFA (1 equiv) was added to induce cyclization and gave 5a exclusively after 16 h at 80 °C (86%, Table , entry 6). However, when expanded to aryl-substituted acylated Meldrum’s acid 2b to access 5b, TFA proved to be inefficient, giving intermediate 4b as the main product (Table , entry 7). p-Toluenesulfonic acid (p-TsOH, 1.5 equiv) proved to be a more efficient reagent and gave the desired 5b in satisfactory yield (75%) (Table , entry 8). Finally, we found that 1 equiv of p-TsOH was also sufficient to produce both 3a and 5a in excellent yields and selectivity (Table , entries 9 and 10, respectively). Finally, to verify the proposed pathway, the β-ketoester formed from 2a and β-ketoamide 4a were isolated and subjected to the optimized conditions, successfully affording 3a and 5a, respectively, in high yield (Scheme S1).

With the optimized conditions in hand, we next investigated the scope of the reaction for the formation of pyrazolo­[1,5-a]­pyrimidin-7-ones (Scheme ). 3a was first synthesized in 81% yield on a 2.5 mmol scale. At this scale, the pure adduct could be obtained analytically after precipitation from the reaction mixture. We next investigated the substitution pattern tolerated on starting acylated Meldrum’s acid 2, using 1a as the model aminopyrazole. Arylated substrates were obtained in good yield, although complete conversion was only achieved upon increasing the amount of 2 to 1.5 equiv (72–87%, 3b–g). Both the electron-donating group and the electron-withdrawing group were well tolerated with a similar reactivity, including the hindered ortho-brominated aryl adduct (87%, 3g). As observed for the arylated derivatives, while ethyl-substituted 3h was obtained in 77% yield under the standard conditions, with secondary alkyl adducts, full conversion and good yields of 3i and 3j could be obtained only with 1.5 equiv of 2 (90% and 84% yields, respectively). We then conducted experiments with a broad range of alkyl adducts. The reaction proved to be compatible and afforded good to excellent yields with sterically hindered groups (84–90%, 3i–k), a thiophene (87%, 3m), a terminal alkene (75%, 3m), a terminal alkyne (77%, 3o), and highly valuable motifs such as an ethyl chloride group (86%, 3p) or a benzyl-protected alcohol (79%, 3q). In parallel, we explored diversification of the substitution pattern of starting aminopyrazole 1. Unsubstituted 3-aminopyrazole underwent cyclocondensation to afford a 69% yield (3r). The 2-cyano-substituted derivative was obtained in high yield (88%, 3u), and substitution at position 1 of the pyrazole ring with a tert-butyl (92%, 3t), a phenyl (70%, 3v), and an ethyl ester (81%, 3w) also showed excellent compatibility under the optimized conditions. However, 3-amino-4-bromopyrazole led to complete decomposition with no trace of product 3s. Likewise, N-alkylated products 3x and 3y were not formed. We next investigated the substrate scope of pyrazolo­[1,5-a]­pyrimidin-5-ones using the same starting materials 1 and 2 (Scheme ). As previously shown for the other regioisomer, the synthesis of analytically pure 5a could be scaled up to 2.5 mmol, affording 5a in very good yield (85%) by simple filtration of the precipitate. With arylated Meldrum’s acid derivatives, using 1.5 equiv of p-TsOH, good yields were obtained with the phenyl (75%, 5b) and electro-donating groups such as p-OMe (87%, 5d) and p-Me (78%, 5f). Electron-withdrawing substituents were also tolerated but gave lower yields, as observed for p-F (60%, 5c) and p-CF3 (50%, 5e) derivatives. Unexpectedly, the ortho-brominated adduct underwent complete degradation under the standard ring-closing conditions (5g). Alkylated acyl-Meldrum’s acids were well tolerated and afforded excellent yields. For instance, target compounds containing ethyl (5h), isopropyl (5i), 1-phenylethyl (5j), methyl-naphthyl (5k), thiophene (5m), terminal alkene (5n), and terminal alkyne (5o) were all obtained in yields exceeding 90%. Chloromethyl adduct 5p was obtained in excellent yield (89%) on a small scale and in good yield (76%) on a 2.5 mmol scale. Benzylated alcohol 5q was also obtained in good yield (73%). When diversifying aminopyrazoles 1, 1-tert-butyl (87%, 5t), 2-cyano (98%, 5u), 1-phenyl (76%, 5v), and 1-ethyl ester (84%, 5w) analogues displayed excellent compatibility under the optimized conditions. In contrast, nonsubstituted (5r) and bromo-substituted (5s) analogues degraded under the standard conditions. Using TFA instead of p-TsOH afforded 5r and 5s in 67% and 58% yields, respectively. Notably, ≈30% of debrominated 5r was isolated, suggesting the acid-promoted debromination of 5s. Disubstitution of the amine was well tolerated in the PP-5-O regioisomer pathway, and N-benzylated adduct 5x was obtained in 88% yield. However, for the N-methylated pyrazole, product 5y was not observed.

2. Substrate Scope.

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a Conditions: 1 (0.25 mmol), 2 (1.2 equiv), and TsOH·H2O (1 equiv) in EtOH (0.25 M) at 80 °C for 16 h in a sealed tube.

b Conditions: (i) 1 (0.25 mmol) and 2 (1.5 equiv) in MeCN (0.25 M) at 80 °C for 1 h and (ii) p-TsOH (1 equiv) at 80 °C for 16 h in a sealed tube.

c 2 (1.5 equiv).

d p-TsOH (1.5 equiv).

e TFA (1 equiv) instead of p-TsOH.

f Debrominated 5r isolated in 33% yield.

h 2 = 2a. n.d., not detected; n.r., no reaction.

We next explored the introduction of a piperidine substituent into both regioisomers, which is a common motif in biologically relevant pyrazolo­[1,5-a]­pyrimidinones. , Acylated Meldrum’s acid 6 was treated under the previously developed conditions using 2 equiv of acid to ensure complete Boc deprotection, affording salts 7 and 9 in good yields (67% and 86%, respectively) after filtration. From a synthetic perspective, retaining the Boc group was advantageous and was achieved by replacing the acid with DIPEA. Compound 10 was obtained in 79% yield (Scheme A), showing that the method is compatible with acid-sensitive substrates. However, attempts to prepare isomer 8 in a good yield were unsuccessful. DIPEA could also be used successfully to obtain model substrate 5a in 71% yield; however, it was unable to circumvent the limitations that we observed in the overall reaction scope (Scheme S2).

3. Piperidine Introduction and Synthetic Utility.

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We also aimed to demonstrate that pyrazolo­[1,5-a]­pyrimidinones can serve as useful intermediates for the preparation of substituted pyrazolo­[1,5-a]­pyrimidines. We performed the chlorination of 3a and 5a, affording derivatives 11 and 13 in 86% and 87% yields, respectively. Chlorinated PPs can be further used in SNAr reactions with nucleophiles, such as amines and thiols, or Pd-catalyzed cross-coupling, to provide disubstituted PPs. To broaden the scope, we investigated dechlorination as a route to monofunctionalized PPs. While dechlorination of 7-chloropyrazolopyrimidines has been reported with moderate yields, no examples of 7-substituted 5-chloropyrazolopyrimidines like 13 have been described. We applied and adapted the hydrodechlorination conditions developed by Sajiki’s group, using palladium on carbon and triethylamine. We found that in ethyl acetate at 0 °C under a hydrogen atmosphere, the palladium-catalyzed hydrodechlorination of compound 11 to PP 12 proceeded smoothly within 1 h. This gave the desired product in 97% yield without any detectable over-reduction of the pyrimidine ring, an issue reported in protic solvents. When applied to compound 13, the reaction required 20 h at room temperature to reach full conversion, affording product 14 in a good 84% yield (Scheme B). Overall, these transformations provide a mild and selective approach to monofunctionalized PPs, further expanding the synthetic utility of PP-O scaffolds.

In summary, we have developed two complementary and robust methods for the regioselective synthesis of functionalized pyrazolo­[1,5-a]­pyrimidinones from 3-aminopyrazoles and acylated Meldrum’s acids. Fine-tuning of the reaction conditions afforded both pyrazolo­[1,5-a]­pyrimidin-5- and -7-ones in high yields with excellent selectivity. These methods provide reliable access to pyrazolo­[1,5-a]­pyrimidin-5-ones, a subclass previously lacking robust synthetic routes. Their simplicity, scalability, and compatibility with diverse substrates make them valuable tools for the generation of biologically relevant derivatives and versatile intermediates. This work also underscores the potential of acylated Meldrum’s acids as efficient building blocks for regioselective functionalization and heterocycle synthesis.

Supplementary Material

ol5c04435_si_001.pdf (6.2MB, pdf)

Acknowledgments

This investigation was supported by grants from the Cancer Research Foundation in Northern Sweden (AMP 24-1154) and the Lion’s Cancer Research Foundation in Northern Sweden (LP 24-2352). Work in the Chorell lab was further supported by the Kempe Foundations (JCK-2139) and the Swedish Research Council (VR-NT 2021-04805). The authors thank Fredrik Almqvist (Department of Chemistry, Umeå University) and his group for generously providing some acylated Meldrum’s acids, Romain Ganivet (Department of Chemistry, Umeå University) for his contribution to the hydrodechlorination of pyrazolo[1,5-a]pyrimidines, and Shaochun Zhu (Department of Chemistry, Umeå University) for HRMS support.

The data underlying this study are available in the published article and its Supporting Information.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c04435.

  • Experimental procedures, NMR (1H and 13C) spectra for all compounds, and HRMS data for the final compounds (PDF)

The authors declare no competing financial interest.

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The data underlying this study are available in the published article and its Supporting Information.

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