BF3-Mediated Acetylation of Pyrazolo[1,5-a]pyrimidines and Other π-Excedent (N-Hetero)arenes.

An operably simple microwave-assisted BF3-mediated acetylation reaction of pyrazolo[1,5-a]pyrimidines and a plausible mechanism based on density functional theory (DFT) theoretical calculations for this transformation are reported. Remarkably, and to the best of our knowledge, this is the first example of the direct acetylation for the functional pyrazolo[1,5-a]pyrimidine (PP) core. The synthesis of this essential building block is reported in high yields using mild reaction conditions, inexpensive reagents, and even substrates with electron-deficient or highly hindered groups. In addition, one of the new methyl ketones was successfully used as a substrate for producing novel and valuable bis-electrophilic compounds with yields of up to 90%. Notably, the discovered acetylation method was successfully applied in other π-excedent (N-hetero)aromatic substrates.

Influence of Steric Effect on the Pseudo-Multicomponent Synthesis of N-Aroylmethyl-4-Arylimidazoles.

A pseudo-three-component synthesis of N-aroylmethylimidazoles 3 with three new C-N bonds formed regioselectively under microwave conditions was developed. Products were obtained by reacting two equivalents of aroylmethyl bromide (ArCOCH2Br, 1) with the appropriate amidine salt (RCN2H3.HX, 2) and with K2CO3 as a base in acetonitrile. The bicomponent reaction also occurred, giving the expected 4(5)-aryl-1H-imidazoles 4. Notably, the ratio of products 3 and 4 is governed by steric factors of the amidine 2 (i.e., R = H, CH3, Ph). Therefore, a computational study was carried out to understand the reaction course regarding product ratio (3/4), regioselectivity, and the steric effects of the amidine substituent group.

Functional Pyrazolo[1,5-a]pyrimidines: Current Approaches in Synthetic Transformations and Uses As an Antitumor Scaffold.

Pyrazolo[1,5-a]pyrimidine (PP) derivatives are an enormous family of N-heterocyclic compounds that possess a high impact in medicinal chemistry and have attracted a great deal of attention in material science recently due to their significant photophysical properties. Consequently, various researchers have developed different synthesis pathways for the preparation and post-functionalization of this functional scaffold. These transformations improve the structural diversity and allow a synergic effect between new synthetic routes and the possible applications of these compounds. This contribution focuses on an overview of the current advances (2015-2021) in the synthesis and functionalization of diverse pyrazolo[1,5-a]pyrimidines. Moreover, the discussion highlights their anticancer potential and enzymatic inhibitory activity, which hopefully could lead to new rational and efficient designs of drugs bearing the pyrazolo[1,5-a]pyrimidine core.

3-Formylpyrazolo[1,5- a]pyrimidines as Key Intermediates for the Preparation of Functional Fluorophores.

A one-pot route for the regioselective synthesis of 3-formylpyrazolo[1,5- a]pyrimidines 4a-k in good yields through a microwave-assisted process is provided. The synthesis proceeds via a cyclocondensation reaction between ß-enaminones 1 with NH-3-aminopyrazoles 2, followed by formylation with an iminium salt moiety (Vilsmeyer-Haack reagent). These N-heteroaryl aldehydes 4 were successfully used as strategic intermediates for the preparation of novel functional fluorophores with yields up to 98%. The structures of the products obtained and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction analysis. Since pyrazolo[1,5- a]pyrimidines (PPs) 3 have shown an important fluorescence, photophysical properties of four 2-methylderivatives substituted at position 7 with different acceptor (A) or donor (D) groups were investigated. The compounds evaluated exhibited large Stokes shift in different solvents, but only the substituted p-methoxyphenyl (4-An) showed a strong fluorescence intensity with quantum yields up to 44% due to its greater ICT. Therefore, hybrid systems based on pyrazolo[1,5- a]pyrimidines could be used as fluorescent probes to detect biologically or environmentally relevant species.

Synthesis of Dicyanovinyl-Substituted 1-(2-Pyridyl)pyrazoles: Design of a Fluorescent Chemosensor for Selective Recognition of Cyanide.

A fluorescence "turn-off" probe has been designed and successfully applied to detect cyanide (CN-) based on a Michael-type nucleophilic addition reaction and intramolecular charge transfer (ICT) mechanism. For this research, a family of 3-aryl-4-(2,2-dicyanovinyl)-1-(2-pyridinyl)pyrazoles as donor-π-acceptor (D-π-A) systems have been synthesized in 58-66% overall yield, by a three-step synthesis sequence starting from p-substituted acetophenones. The substituted p-methoxyphenyl showed good fluorescence emission and large Stokes shifts in different solvents due to its greater ICT. Likewise, this probe evidenced high selectivity and sensitivity and fast recognition for CN- with a detection limit of 6.8 µM. HRMS analysis, 1H NMR titration experiments, and TD-DFT calculations were performed to confirm the mechanism of detection and fluorescence properties of the chemodosimeter of CN-. Additionally, fluorescent test paper was conveniently used to detect cyanide in aqueous solution.

One-Step Synthesis of Fully Functionalized Pyrazolo[3,4-b]pyridines via Isobenzofuranone Ring Opening.

A novel series of fully substituted pyrazolo[3,4-b]pyridines 4 has been prepared in a regioselective manner by the microwave-assisted reaction between N-substituted 5-aminopyrazoles 1 and 3-(3-oxo-2-benzofuran-1(3H)-ylidene)pentane-2,4-dione (2). This is the second reported example of a cyclocondensation reaction using substrate 2 as a 1,3-bis-electrophilic reagent. Remarkably, this synthesis offers functionalized products with acetyl and carboxyl groups in one step, in good yields, and with short reaction times. Additionally, the cyclization intermediate 3 was isolated, allowing us to postulate a mechanism for this reaction, which is initiated via isobenzofuranone ring opening of 2 in a Michael-type reaction. The structures of the products and regioselectivity of the reactions were determined on the basis of NMR measurements and X-ray diffraction. For this new reaction using substrate 2, the optimal reaction conditions and its scope were investigated.

6-(Aryldiazenyl)pyrazolo[1,5-a]pyrimidines as Strategic Intermediates for the Synthesis of Pyrazolo[5,1-b]purines.

A microwave-assisted approach for the regioselective synthesis of functionalized 6-(aryldiazenyl)pyrazolo[1,5-a]pyrimidin-7-amines from the cyclization of 3-oxo-2-(2-arylhydrazinylidene)butanenitriles with 5-amino-1H-pyrazoles under solvent-free conditions has been developed. This methodology was distinguished by its broad substrate scope, operational simplicity, high atom economy, and high-yielding without requiring chromatographic purification. In addition, an efficient and versatile palladium-catalyzed reductive azo cleavage is disclosed for the synthesis of diverse heteroaromatic 1,2-diamines, a valuable synthetic building block to develop new fused heteroaromatic systems. As synthetic example, several substituted pyrazolo[5,1-b]purines were synthesized in yields up to 96% by using microwave irradiation in the cyclocondensation of these 1,2-diamines with orthoesters.

Microwave-assisted synthesis and functionalization of 2-arylimidazo[1,2-a]pyrimidin-5(8H)-ones.

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.

Cs2CO3-Promoted Alkylation of 3-Cyano-2(1H)-pyridones: Anticancer Evaluation and Molecular Docking.

Herein, a Cs2CO3-promoted N-alkylation of 3-cyano-2(1H)-pyridones containing alkyl groups with diverse alkyl halides to synthesize N-alkyl-2-pyridones over O-alkylpyridines is reported. Alkyl dihalides resulted in complex mixtures of N- and O-alkylated products. The primary factor influencing regioselectivity in these reactions is the electronic effects of substituents on the 2(1H)-pyridone ring, as evidenced by the preferential formation of O-alkylpyridines upon the introduction of aryl groups. Remarkably, we efficiently employed CuAAC and Ti(Oi-Pr)4-catalyzed amidation reactions to functionalize N-alkyl-2-pyridones containing propargyl and ester groups, leading to the synthesis of 1,2,3-triazoles and amides, respectively. Moreover, O-alkylpyridines 10b and 10d displayed remarkable selectivity toward the A-498 renal cancer cell line with growth inhibition percentages (%GI) of 54.75 and 67.64, respectively. The binding modes of compounds 10b and 10d to the PIM-1 kinase enzyme were determined through molecular docking studies.

5-Methyl-N-[2-nitro-4-(trifluoromethyl)phenyl]-1H-pyrazole-3-amine: a chain of hydrogen-bonded R(2)(2)(6) and R(2)(2)(16) rings.

The molecular skeleton of the title compound, C(11)H(9)F(3)N(4)O(2), is almost planar and exhibits a polarized (charge-separated) electronic structure in the nitroaniline portion. Molecules are linked by N-H···N and C-H···O hydrogen bonds to form a chain in which centrosymmetric R(2)(2)(6) and R(2)(2)(16) rings alternate.

Current Advances in Diazoles-based Chemosensors for CN- and FDetection.

Advances in molecular probes have recently intensified because they are valuable tools in studying species of interest for human health, the environment, and industry. Among these species, cyanide (CN-) and fluoride (F-) stand out as hazardous and toxic ions in trace amounts. Thus, there is a significant interest in probes design for their detection with diverse diazoles (pyrazole and imidazole) used for this purpose. These diazole derivatives are known as functional molecules because of their known synthetic versatility and applicability, as they exhibit essential photophysical properties with helpful recognition centers. This review provides an overview of the recent progress (2017-2021) in diazole-based sensors for CN- and F- detection, using the azolic ring as a signaling or recognition unit. The discussion focuses on the mechanism of the action described for recognizing the anion, the structure of the probes with the best synthetic simplicity, detection limits (LODs), application, and selectivity. In this context, the analysis involves probes for cyanide sensing first, then probes for fluoride sensing, and ultimately, dual probes that allow both species recognition.

Synthesis of structural analogues of Reversan by ester aminolysis: an access to pyrazolo[1,5-a]pyrimidines from chalcones.

Reversan, a multidrug resistance-associated protein (MRP1) inhibitor described more than a decade ago, is a commercial drug (CAS: 313397-13-6) that has a high price and is six to eight times more potent than known drug transporter inhibitors. However, to date, a complete route for synthesizing pyrazolo[1,5-a]pyrimidine-based Reversan is yet to be published. Herein, the silica gel-mediated synthesis of Reversan and a novel family of its structural analogues (amides) via the microwave-assisted amidation reaction of 3-carboethoxy-5,7-diphenylpyrazolo[1,5-a]pyrimidine (ester) with primary amines is reported. Moreover, a set of this ester-type precursor was obtained using the NaF/alumina-mediated reaction of 5-amino-3-carboethoxy-1H-pyrazole with chalcones, implying a final removal of H2 using Na2S2O8. Both esters and amides were obtained in high yields using heterogeneous catalyst and solvent-free, highly efficient, and scalable synthetic protocols.

Photophysical and anion sensing properties of a triphenylamine-dioxaborinine trimeric compound.

Herein, we report the synthesis and photophysical characterization of the novel tris(4-(2,2-difluoro-6-methyl-2H-1λ3,3,2λ4-dioxaborinin-4-yl)phenyl)amine trimeric probe (A2) via the reaction between triphenylamine (1), acetic anhydride, and BF3·OEt2 implying the twelve new bond formation in a one-pot manner. This highly fluorescent compound in solution (φ up to 0.91 at 572 nm) and solid state (φ = 0.24 at 571 nm) showed a better solvatofluorochromism than its analog monomeric A1 due to symmetry-broken charge transfer, which is consistent with high solvent dipolarity (SdP) response in Catalán's multiparametric regression. Notably, A2 had a high sensibility and selectivity for CN- or F- in solution (LODCN-/F- = 0.18/0.70 µM), and CN- can be discriminated from F- by the reaction of A2 with 3.0 equiv. of CN-. In addition, A2 was impregnated on filter paper to prepare test strips that were applied to naked-eye qualitative sensing of CN- or F-. Finally, the octupolar system in A2 allows for better action of two-photon excitation cross-section values when compared with that of the dipolar structure in A1. These findings provide further information for the design of new efficient two-photon absorption dyes.

A π-stacked chain of hydrogen-bonded dimers in 3-tert-butyl-1-(4-chlorophenyl)-4-phenylindeno[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one and a π-stacked sheet of hydrogen-bonded chains in 3-tert-butyl-1-(4-chlorophenyl)-4-(4-methoxyphenyl)indeno[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one.

In 3-tert-butyl-1-(4-chlorophenyl)-4-phenylindeno[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one, C(29)H(22)ClN(3)O, (I), inversion-related pairs of molecules are linked by C-H...O hydrogen bonds to form R(2)(2)(18) dimers, which are themselves linked into a chain by a π-π stacking interaction between inversion-related pairs of molecules. In 3-tert-butyl-1-(4-chlorophenyl)-4-(4-methoxyphenyl)indeno[1,2-b]pyrazolo[4,3-e]pyridin-5(1H)-one, C(30)H(24)ClN(3)O(2), (II), which crystallizes in the space group P-1, with Z' = 2 and with different orientations for the methoxy groups in the two independent molecules, a combination of C-H···O and C-H···π(arene) hydrogen bonds links the molecules into chains of rings, which are further linked into sheets by a π-π stacking interaction.

Chemosensors based on N-heterocyclic dyes: advances in sensing highly toxic ions such as CN- and Hg2.

CN- and Hg2+ ions are harmful to both the environment and human health, even at trace levels. Thus, alternative methods for their detection and quantification are highly desirable given that the traditional monitoring systems are expensive and require qualified personnel. Optical chemosensors (probes) have revolutionized the sensing of different species due to their high specificity and sensitivity, corresponding with their modular design. They have also been used in aqueous media and different pH ranges, facilitating their applications in various samples. The design of molecular probes is based on organic dyes, where the key species are N-heterocyclic compounds (NHCs) due to their proven photophysical properties, biocompatibility, and synthetic versatility, which favor diverse applications. Accordingly, this review aims to provide an overview of the reports from 2016 to 2021, in which fluorescent probes based on five- and six-membered N-heterocycles are used for the detection of CN- and Hg2+ ions.

A simple hydrogen-bonded chain in (3Z)-3-{1-[(5-phenyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one, and a hydrogen-bonded ribbon of centrosymmetric rings in the self-assembled adduct (3Z)-3-{1-[(5-methyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4H)-one (1/1).

(3Z)-3-{1-[(5-Phenyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one, C(15)H(15)N(3)O(2), (I), and the stoichiometric adduct (3Z)-3-{1-[(5-methyl-1H-pyrazol-3-yl)amino]ethylidene}-4,5-dihydrofuran-2(3H)-one-6-(2-hydroxyethyl)-2,5-dimethylpyrazolo[1,5-a]pyrimidin-7(4H)-one (1/1), C(10)H(13)N(3)O(2).C(10)H(13)N(3)O(2), (II), in which the two components have the same composition but different constitutions, are formed in the reactions of 2-acetyl-4-butyrolactone with 5-amino-3-phenyl-1H-pyrazole and 5-amino-3-methyl-1H-pyrazole, respectively. In each compound, the furanone component contains an intramolecular N-H...O hydrogen bond. The molecules of (I) are linked into a chain by a single intermolecular N-H...O hydrogen bond, while in (II), a combination of one O-H...N hydrogen bond, within the selected asymmetric unit, and two N-H...O hydrogen bonds link the molecular components into a ribbon containing alternating centrosymmetric R(4)(4)(20) and R(6)(6)(22) rings.

7-Amino-5-methyl-2-phenyl-6-(phenyldiazenyl)pyrazolo[1,5-a]pyrimidine crystallizes with Z' = 2: pseudosymmetry and the formation of complex sheets built from N-H...N and C-H...pi(arene) hydrogen bonds.

The title compound, C(19)H(16)N(6), crystallizes with Z' = 2 in the space group P2(1)/n. The two molecules in the selected asymmetric unit are approximate mirror images of one another; most corresponding pairs of atoms are related by an approximate half-cell translation along [100]. Each molecule contains an intramolecular N-H...N hydrogen bond and the molecules are linked into complex sheets by a combination of two intermolecular N-H...N and four C-H...pi(arene) hydrogen bonds. Comparisons are made with some other 7-aminopyrazolo[1,5-a]pyrimidines.

5-Amino-1-benzoyl-3-methylpyrazole: complex sheets built from N-H...N, C-H...O and C-H...pi(arene) hydrogen bonds.

Molecules of the title compound [systematic name: (5-amino-3-methylpyrazol-1-yl)(phenyl)methanone], C(11)H(11)N(3)O, contain an intramolecular hydrogen bond. The molecules are linked into sheets by a combination of N-H...N, C-H...O and C-H...pi(arene) hydrogen bonds. Comparisons are made with the hydrogen-bonded structures of some related compounds.

Recent progress in chemosensors based on pyrazole derivatives.

Colorimetric and fluorescent probes based on small organic molecules have become important tools in modern biology because they provide dynamic information concerning the localization and quantity of the molecules and ions of interest without the need for genetic engineering of the sample. In the past five years, these probes for ions and molecules have attracted great attention because of their biological, environmental and industrial significance combined with the simplicity and high sensitivity of absorption and fluorescence techniques. Moreover, pyrazole derivatives display a number of remarkable photophysical properties and wide synthetic versatility superior to those of other broadly used scaffolds. This review provides an overview of the recent (2016-2020) findings on chemosensors containing pyrazole derivatives (pyrazoles, pyrazolines and fused pyrazoles). The discussion focuses on the design and physicochemical properties of chemosensors in order to realize their full potential for practical applications in environmental and biological monitoring (sensing of metal ions, anions, explosives, and biomolecules). We also present our conclusions and outlook for the future.

Cyanide chemosensors based on 3-dicyanovinylpyrazolo[1,5-a]pyrimidines: Effects of peripheral 4-anisyl group substitution on the photophysical properties.

Novel dual-mode colorimetric/fluorometric probes based on 3-dicyanovinylpyrazolo[1,5-a]pyrimidines for cyanide (CN-) sensing have been developed (DPPa-c). These probes displayed high selectivity and sensitivity toward CN- over other interfering anions, with a detection limit (LOD) as low as 610/170 nmol L-1 (absorption/emission) for some of the prepared probes. After a reaction with CN-, low-fluorescent DPPa-c showed a significant decrease of the intramolecular charge transfer (ICT) bands at approximately 390 nm (color changes from yellow to colorless) and exhibited up to an 82-fold fluorescence enhancement at approximately 465 nm (strong blue-light emission). The successive introduction of 4-anisyl (4-MeOPh) groups on periphery of the heterocyclic core had a dramatic influence on both the photophysical properties and CN- detection capability. The number of channels for CN- quantification in the absorption spectra increased from 1 in DPPa to 3 in DPPc. Moreover, the fluorescence emission LOD decreased from 300 nmol L-1 in DPPa to 170 nmol L-1 in DPPc. Finally, the selectivity toward CN- demonstrated a notable improvement when the probe had three 4-anisyl groups in its periphery (i.e., DPPc).