Synthesis and Characterization of New Pyrano[2,3-c]pyrazole Derivatives as 3-Hydroxyflavone Analogues

Abstract

In this paper, an efficient synthetic route from pyrazole-chalcones to novel 6-aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones as 3-hydroxyflavone analogues is described. The methylation of 5-hydroxy-2,6-phenylpyrano[2,3-c]pyrazol-4(2H)-one with methyl iodide in the presence of a base yielded a compound containing a 5-methoxy group, while the analogous reaction of 5-hydroxy-2-phenyl-6-(pyridin-4-yl)pyrano[2,3-c]pyrazol-4(2H)-one led to the zwitterionic 6-(N-methylpyridinium)pyrano[2,3-c]pyrazol derivative. The treatment of 5-hydroxy-2,6-phenylpyrano[2,3-c]pyrazol-4(2H)-one with triflic anhydride afforded a 5-trifloylsubstituted compound, which was further used in carbon–carbon bond forming Pd-catalyzed coupling reactions to yield 5-(hetero)aryl- and 5-carbo-functionalized pyrano[2,3-c]pyrazoles. The excited-state intramolecular proton transfer (ESIPT) reaction of 5-hydroxypyrano[2,3-c]pyrazoles from the 5-hydroxy moiety to the carbonyl group in polar protic, polar aprotic, and nonpolar solvents was observed, resulting in well-resolved two-band fluorescence. The structures of the novel heterocyclic compounds were confirmed by ¹H-, ¹³C-, ¹⁵N-, and ¹⁹F-NMR spectroscopy, HRMS, and single-crystal X-ray diffraction data.

1. Introduction

Fused pyrazole derivatives represent an important class of organic compounds as they are found in a large number of biologically and chemically active compounds [1]. These compounds are known for their anticancer [2], antimicrobial [3], antiviral [4], and anti-coagulant properties [5], and for their activity against CNS disorders [6]. Some of the fused pyrazole moieties are present in marketed drugs, such as apixaban, sildenafil, indiplon, zaleplon, etazolate, cartazolate, allopurinol, and futibatinib, which was recently approved by the U.S. Food and Drug Administration (FDA) [7].

Among other fused systems, pyrano[2,3-c]pyrazoles have been investigated for analgesic and anti-inflammatory [8], antimicrobial [9,10], and anticancer [11] activities. Recently, Sun et al. described the nano-formulation and anticancer activity of a 6-amino-4-(2-hydroxyphenyl)-3-methyl-1,4-dihydropyrano[2,3-c]pyrazole-5-carbonitrile via the blocking of the cell cycle through a p53-independent pathway [12], while Nguyen et al. reported a four-component sulfonated amorphous carbon and eosin Y-catalyzed synthesis and the molecular docking of 6-amino-1,4- or 2,4-dihydropyrano[2,3-c]pyrazole-5-carbonitriles as inhibitors of p38 MAP kinase [13]. In our previous studies, we reported the synthesis, characterization, and biological evaluation of several pyrano[2,3-c]pyrazole derivatives [14,15]. However, 5-hydroxy-2,6-diarylpyrano[2,3-c]pyrazol-4(2H)-ones, which can serve as potential analogues of 3-hydroxyflavone, are still understudied.

3-Hydroxyflavone I (Figure 1) is known as the backbone of all flavonols. Flavonols are a class of the flavonoid family, a group of naturally occurring substances with variable phenolic structures, found in fruits, vegetables, grains, bark, roots, stems, flowers, tea, and wine [16,17,18]. Quercetin II and kaempferol III (Figure 1) are the most prevalent in plants and are among the flavonols that have been most investigated and reviewed for beneficial health properties, such as antioxidant, antimicrobial, hepatoprotective, and anti-inflammatory properties, and other effects [19,20]. Synthetic and semisynthetic flavonol derivatives have been reported in the literature in an attempt to improve the biochemical and pharmacological properties of their corresponding natural compounds. For example, synthesis and anti-Leishmania activity were reported for benzothiophene-flavonols [21]. A series of spirochromone-flavonols [22] and thiophene-pyrazole-flavonols [23] was synthesized and tested as antimicrobial agents. In addition, flavonols containing an isothiazolidine ring have been found to be effective inhibitors of cyclin-dependent kinase 2 (CDK2) [24].

3-Hydroxyflavones are known as fluorescent dyes because of their typical excited-state intramolecular photon transfer (ESIPT). ESIPT is one type of proton transfer reaction that has been the subject of considerable interest and a number of investigations in recent decades [25,26]. 3-Hydroxyflavones have been investigated as therapeutic imaging agents, including as fluorescence sensors and probes for the detection of the microenvironment, metal ions, and structures of proteins and DNA [27,28,29,30]. For example, Jiang et al. reported the application of 3-hydroxyflavone-based ESIPT fluorescent dyes for the dynamic imaging of lipid droplets with cells and tissues [31]. In a study by Kamariza et al., a 3-hydroxychromone derivative, 2-[7-(diethylamino)-9,9-dimethyl-9H-fluoren-2-yl]-3-hydroxy-4H-chromen-4-one, was conjugated to trehalose and a bright solvatochromic dye was obtained that detects Mycobacterium tuberculosis in a matter of minutes [32].

The O-methylation of 3-hydroxyflavones with reagents such as diazomethane, methyl iodide, dimethyl sulfate, or dimethyl carbonate proceeded to give O-methylated flavonoids, which exhibited a variety of biological activities [33,34,35]. For example, Ohtani et al. investigated the effect of 3-methoxyflavone derivatives, such as those of compound IV (Figure 1), on P-glycoprotein by measuring the potentiation of cellular accumulation and growth inhibition [36]. Juvale et al. reported the inhibitory activity of 3-methoxyflavones against a breast cancer resistance protein (BVRP/ABCG2) [37]. Furthermore, 3-hydroxyflavone treated with p-TsCl in the presence of a base afforded a corresponding flavone tosylate V, which was used in a Suzuki–Miyaura reaction for cross coupling with various phenyl boronic acids to give 2,3-diarylbenzopyrans [38,39]. Flavone-like 2,3-diarylbenzopyrans, such as compound VI (Figure 1), have been synthesized as novel selective inhibitors of cyclooxygenase-2 [40,41].

In the continuation of our research on the development of novel fused heterocyclic pyrazole-containing systems, we report here the synthesis, structural elucidation, and optical properties of novel 6-aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one derivatives as analogues of 3-hydroxyflavones. The ESIPT reaction of 6-aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones from the 5-hydroxy moiety to the carbonyl group in MeOH and polar aprotic and non-polar solvents was also investigated. The obtained 5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones were further functionalized by methylation as well as the Pd-catalyzed Suzuki, Heck, and Sonogashira coupling reactions of intermediate 5-triflate.

2. Results and Discussion

2.1. Chemistry

The synthesis of 6-(hetero)aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones 3a–h was carried out as depicted in Scheme 1. 1-Phenyl-1H-pyrazol-3-ol 1 was obtained using a previously reported method [42,43] and subjected to a Claisen–Schmidt condensation reaction with variously 4′-substituted (hetero)aryl aldehydes in the presence of ethanolic sodium hydroxide, as we have described [44]. Heating the reaction mixture at 55 °C for 3 to 5 h afforded (E)-1-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 2a–h in poor to excellent yields (36–95%).

In a subsequent step, an Algar–Flynn–Oyamada (AFO) synthetic approach was applied for the formation of novel pyrano[2,3-c]pyrazol-4(2H)-ones 3a–h. The AFO reaction is a stepwise process whereby chalcones undergo an oxidative cyclization to form flavones in the presence of alkaline hydrogen peroxide [45]. The AFO reaction outcome is dependent on the choice of the base; therefore, chalcone 2a was used as a model compound for the fine-tuning of the reaction conditions. Several organic and inorganic bases (NaOH, KOH, NaOAc, TEA, and NaHCO₃) were screened in different mixtures of ethanol/water as a solvent and a divergent amount of hydrogen peroxide (Table S1). The best result was obtained when using NaOH in EtOH and employing 5 eq of H₂O₂. Stirring chalcones 2a–h with hydrogen peroxide in an alkaline ethanolic solution at −25 °C for 2 h and at room temperature overnight afforded the flavonol analogues 3a–h in poor to good yields (30–67%). The pyrano[2,3-c]pyrazol-4(2H)-ones 3e and 3g were obtained in lower yields (30–32%) when chalcones bearing naphtalen-2-yl or furan-3-yl substituents (2e and 2g, respectively) were used as starting materials in the AFO reaction. Unfortunately, the AFO reaction of (E)-3-(4-fluorophenyl)-1-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one or its 3-(4-nitrophenyl) counterpart gave only traces of targeted pyrano[2,3-c]pyrazol-4(2H)-ones.

According to the mechanistic studies reported in the literature [45,46,47], the formation of 6-(hetero)aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones 3 from (E)-1-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones 2, employing AFO reaction conditions could proceed according to two different pathways, as depicted in Figure 2, using the transformation of 2a to 3a as an example. According to the approach suggested by Shen et al., first epoxide A (Figure 2, path A) is formed; then it is subsequently cyclized to 5-hydroxy-2,6-diphenyl-5,6-dihydropyrano[2,3-c]pyrazol-4(2H)-one B and oxidized to target 5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one 3a [45]. Alternatively, as suggested by Ferreira et al., pyrazole-chalcone 2a might first undergo a cyclization forming a 2,6-diphenyl-2,6-dihydropyrano[2,3-c]pyrazol-4-olate C (Figure 2, path B), followed by an attack of hydrogen peroxide and subsequent oxidation to form 3a [47].

For further modification of the obtained flavanol analogue 3a, O-alkylation reaction conditions were applied. As a result, treating 3a with methyl iodide in the presence of cesium carbonate in dioxane at 40 °C gave O-methylated compound 4 in a 79% yield (Scheme 2).

Subsequently the methylation of compound 3h containing both the hydroxyl group and the pyridin-4-yl substituent was investigated (Scheme 3). With the alkylation reaction conditions described above (MeI, Cs₂CO₃, dioxane, 40 °C), a formation of zwitterionic pyrano[2,3-c]pyrazol derivative 5 as the main product was observed.

The proposed mechanism for the formation of compound 5 is shown in Scheme 3. Presumably, first, as a result of the reaction of pyridinyl-containing compound 3h with methyl iodide, methylpyridinium iodide 6 was formed. This was also demonstrated when alkylating compound 3h in the absence of a base as salt 6 was obtained in a 78% yield. The subsequent treatment of methylpyridinium iodide 6 with a base led to the formation of methylpyridinium hydroxide Y, which, upon the removal of the water molecule, led to the formation of the corresponding structure 5 as a resonance hybrid with the two contributing forms A and B, zwitterionic and neutral molecular structures, respectively. Pat et al. investigated the two-photon absorption (TPA) processes in a class of 4-quinopyran chromophores. The neutral molecular structure with a quinoid geometry is the molecular ground state, while the zwitterionic configuration with a benzenoid structure contributes significantly. The bond connecting the donor and acceptor phenylene fragments is a double bond when the molecule is neutral, while it is a single bond for the zwitterionic structure [48].

Further functionalization of pyrano[2,3-c]pyrazol-4(2H)-ones was accomplished via O-triflate intermediate 7, which was synthesized from 5-hydroxy-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (3a) following a standard procedure using Tf₂O in the presence of TEA (Scheme 4). The obtained 4-oxo-2,4-dihydropyrano[2,3-c]pyrazol-5-yl trifluoromethanesulfonate 7 was subjected to Suzuki, Heck, and Sonogashira reactions to examine the employment of Pd-catalyzed coupling reactions for the functionalization of pyrano[2,3-c]pyrazol-4(2H)-ones. Triflate 7 underwent Suzuki-type cross coupling with (hetero)aryl boronic acids to give compounds 8a–e in fair to excellent yields (44–95%). In the course of this coupling, standard conditions were applied, i.e., Pd(PPh₃)₄ was used as a catalyst and anhydrous K₃PO₄ as a base in dioxane at 90 °C. The reaction was carried out in the presence of KBr, which is known to suppress the decomposition of the palladium catalyst transition state by converting phosphonium salts to palladium bromide [49]. The Suzuki reaction yield was lower (44%) when 4-chlorophenylboronic acid was used for the cross coupling.

The Heck reaction of triflate 7 and tert-butyl acrylate under the standard conditions (Pd(PPh₃)₂Cl₂, TEA, DMF, 100 °C) gave a poor yield (24%) of tert-butyl (E)-3-(4-oxo-2,4-dihydropyrano[2,3-c]pyrazol-5-yl)acrylate 8f, while the Sonogashira cross-coupling reaction of compound 7 with phenylacetylene under the usual conditions (Pd(PPh₃)₂Cl₂, CuI, TEA, DMF, 65 °C) afforded alkyne 8g in a good yield (71%). A similar approach of flavonol functionalization employing Pd-catalyzed reactions of O-triflates was also reported by Kumar et al. in their study on the synthesis of 3,4-diarylpyrazoles and 4,5-diarylpyrimidines, starting with triarylbismuth as a three-fold arylating reagent and 3-trifloxychromones [50]. Dahlén et al. reported a synthetic strategy to form 2,3,6,8-tetrasubstituted chromone derivatives employing a Stille coupling reaction for the functionalization of the third position of the ring via intermediate 4-oxo-4H-chromen-3-yl trifluoromethanesulfonates [51]. Notably, it was observed that the latter compounds were not active under Heck reaction conditions. In addition, Akwari et al. demonstrated effective 3-arylation of flavones via a Suzuki cross-coupling reaction of 3-(trifluorosulphonyloxy)flavone [52].

2.2. NMR Spectroscopic Investigations

The formation of 6-(hetero)aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-ones 3a–h and their derivatives 4, 5, 6, 7, and 8a–g was confirmed through detailed analysis of their spectroscopic data. Key information for structure elucidation was obtained from NMR spectral data using a combination of standard and advanced NMR spectroscopy techniques, such as ¹H-¹³C HMBC, ¹H-¹³C LR-HSQMBC, ¹H-¹⁵N HMBC, ¹H-¹³C HSQC, ¹H-¹³C H2BC, ¹H-¹H COSY, ¹H-¹H TOCSY, ¹H-¹H NOESY, and 1,1-ADEQUATE experiments. Since popular NMR prediction programs such as CSEARCH, ACD C+H predictor, as well as NMR chemical shift databases for structural dereplication depend on high-quality data with unambiguously assigned resonances [53], we carried out NMR studies with the obtained compounds to fully map all the ¹H, ¹³C and ¹⁵N NMR signals as accurately as possible. The corresponding NMR data for the selected representatives of the aforementioned new ring systems are displayed in Figure 3 and Figure 4.

An initial comparison of the ¹H NMR spectra between chalcone 2a and compound 3a, which was isolated as the sole product, clearly indicated the disappearance of characteristic olefinic protons (δ 7.63 and 7.75 ppm) from the prop-2-en-1-one moiety. Furthermore, the ¹³C NMR and DEPT, along with the ¹H-¹³C HSQC spectroscopic data of 3a, revealed the presence of two new quaternary carbons (δ 139.16 and 144.4 ppm) in the absence of two olefinic methine carbons, clearly indicating a successful oxidative cyclization to flavanol. The structure of the pyrano[2,3-c]pyrazol-4(2H)-one ring system 3a bearing phenyl substituents at sites N-2 and C-6 was further elucidated via the connectivities based on the through-space correlations from the ¹H-¹H NOESY spectrum. In this case, distinct NOEs were exhibited between the pyrazole ring proton 3-H (singlet, δ 9.38 ppm) and the neighboring phenyl group 2′(6′)-H protons (δ 8.01–8.03 ppm), which confirms their proximity in space. The pyrazole 3-H proton was easily distinguished as it exhibited not only long-range HMBC correlations with neighboring N-2 “pyrrole-like” (δ −167.7 ppm) and N-1 “pyridine-like” (δ −117.0 ppm) nitrogen atoms, but also HMBC correlations with the quaternary carbons C-3a (δ 108.3 ppm) and C-7a (δ 161.2 ppm), respectively. The quaternary carbons C-5 (δ 139.16 ppm) and C-6 (δ 144.4 ppm) were assigned by comparing the long-range correlations obtained from the ¹H-¹³C HMBC and ¹H-¹³C LR-HSQMBC spectra. The most downfield and significantly broadened ¹H signal resonating at δ 9.44 ppm was attributed to the hydroxyl group as it lacked correlations in the HSQC spectra. Finally, by process of elimination, the most downfield ¹³C signal resonating at δ 171.8 ppm was confidently assigned to the carbonyl carbon, thus completing our assignment of the pyrano[2,3-c]pyrazol-4(2H)-one ring system. An in-depth analysis of NMR spectral data showed that the chemical shift values were highly consistent within the flavonol analogues 3a–h, thus validating the shifts for each position (Table S2).

The presence of a hydroxyl group at site 5 was further confirmed by the conversion of 3a to O-methylated and O-triflated derivatives 4 and 7, respectively. While the structural elucidation of O-methylated compound 4 was straightforward and followed the same logical approach as in the case of compounds 3a–h, additional distinct NOEs were observed between the methoxy group protons (δ 3.77 ppm) and the neighboring phenyl group 2″(6″)-H protons (δ 7.96–7.98 ppm). The formation of O-triflated derivative 7 was clearly distinguished from the ¹³C NMR spectrum, where the CF₃ group was observed as a quartet at δ 118.2 ppm (q, ¹J_CF = 320.8 Hz). Moreover, the ¹⁹F NMR spectrum revealed a chemical shift of the CF₃ group at δ −74.0 ppm, which is in good agreement with the data reported in the literature [54,55]. The triflate intermediate 7 underwent Pd-catalyzed coupling reactions to give derivatives 8a–g, whose structures were also unambiguously elucidated. For instance, compound 8f was obtained as an E-isomer. The magnitude of the vicinal coupling between the olefinic protons H_a (δ 7.35 ppm) and H_b (δ 7.31 ppm), which exhibited an AB-spin system and appeared as two sets of doublets (³J_Ha,Hb = 15.9 Hz), unquestionably confirmed E-configuration at the C=C double bond. Lastly, the olefinic protons were easily discriminated as only the proton H_a exhibited long-range ¹H-¹³C HMBC correlations with neighboring C-4, C-5, and C-6 quaternary carbons (Figure 3).

The NMR spectral data of compound 3h with a pyridine moiety at site 6 revealed similar chemical shifts in the pyrano[2,3-c]pyrazol-4(2H)-one ring system compared with 3a–g. The ¹H-¹⁵N HMBC spectrum revealed a new downfield ¹⁵N signal resonating at δ −62.2 ppm in addition to N-2 “pyrrole-like” (δ −166.9 ppm) and N-1 “pyridine-like” (δ −117.1 ppm) nitrogen atoms from the pyrazole moiety. The formation of methylpyridinium iodide 6 via the alkylation of 3h was unambiguously confirmed from the ¹H-¹⁵N HMBC and ¹H-¹H NOESY spectral data. For instance, distinct NOEs were observed between the methyl group protons (δ 4.39 ppm) and the neighboring pyridinium 2″(6″)-H protons (δ 9.03 ppm). The aforementioned protons revealed strong long-range correlations with the methylpyridinium nitrogen at δ −183.3 ppm, which is in good agreement with the data reported in the literature [56].

In the case of compound 5, which can exist in two resonant forms, the ¹H-¹⁵N HMBC spectrum revealed a new upfield ¹⁵N signal resonating at δ −214.4 ppm. Furthermore, distinct ¹H and ¹³C signals, which appeared to be broadened, were also observed (sites 2″, 3″, 5″, and 6″). Additionally, the key information for the structure elucidation of compounds 3h, 5, and 6 was obtained after an in-depth analysis of the long-range correlations in the ¹H-¹³C HMBC, ¹H-¹³C H2BC, and ¹H-¹³C LR-HSQMBC spectra (Figure 4) [57].

Figure 4. Relevant ¹H-¹³C HMBC, ¹H-¹³C LR-HSQMBC, ¹H-¹³C H2BC, ¹H-¹⁵N HMBC, ¹H-¹H NOESY, and 1,1-ADEQUATE correlations, as well as ¹H NMR (italics), ¹³C NMR, and ¹⁵N NMR (bold) chemical shifts of compounds 3h (DMSO-d₆), 5 (DMSO-d₆), and 6 (DMSO-d₆).

Figure 4. Relevant ¹H-¹³C HMBC, ¹H-¹³C LR-HSQMBC, ¹H-¹³C H2BC, ¹H-¹⁵N HMBC, ¹H-¹H NOESY, and 1,1-ADEQUATE correlations, as well as ¹H NMR (italics), ¹³C NMR, and ¹⁵N NMR (bold) chemical shifts of compounds 3h (DMSO-d₆), 5 (DMSO-d₆), and 6 (DMSO-d₆).

Then, we carried out NMR studies of compounds 3h and 5 at 25 °C in TFA-d solutions (Scheme 5) to convert them to pyridinium and methylpyridinium trifluoroacetates 9 and 10, respectively. The ¹⁵N NMR spectral data confirmed that it was easily achieved as “pyridinium-like” ¹⁵N signals comparable to compound 6 resonating at δ −189.2 ppm and δ −183.2 ppm were observed. Moreover, in the case of compound 10, which was obtained from compound 5, the broadening of the ¹H and ¹³C signals was absent.

2.3. Single-Crystal X-ray Diffraction Analysis

The asymmetric molecular structure of compound 5 is shown in Figure 5a. The single crystal is composed of compound 5 solvated with molecules of methanol. The methanol formed hydrogen bonds in the monocrystal of 5, including the hydrogen link to the O(15) (the H^…O length is 1.917 Å) (Table S6). The intramolecular hydrogen bond is also observed between the O(15) enolate oxygen and the C(17)–H(17) hydrogen atom (the H^…O length is 2.207 Å). The main core of compound 5 consists of the planar pyrano[2,3-c]pyrazole ring system, which possesses phenyl and the pyridin-4-yl substituents at N(2) and C(6), respectively. These substituents are slightly distorted from the pyrano[2,3-c]pyrazole plane. The phenyl ring is turned approx. 10° and the pyridinyl ring for approx. 6° counterclockwise when looking outward from the core. The N(19)–C(22) bond length of the N-methylpyridinium moiety is 1.4737(14) Å (Table S9), and the C(17)–C(18) and C(20)–C(21) bond lengths are 1.3721(15) and 1.3633(16) Å, respectively, and agree with the known bond lengths of the N-methylpyridynium salts [58]. All atoms of the pyridine moiety are located in the same plane in agreement with the data reported in the literature [59].

The selected bond lengths and angles of the pyrano[2,3-c]pyrazole ring are shown in

Table 1. Selected bond lengths [Å] for compound 5.

Atom	Atom	Length/Å	Atom	Atom	Length/Å
N1	N2	1.3839(12)	C4	C5	1.5140(14)
N1	C7A	1.3233(14)	C4	O14	1.2265(14)
N2	C3	1.3458(14)	C5	C6	1.4047(15)
N2	C8	1.4287(13)	C5	O15	1.2723(13)
C3	C3A	1.3842(14)	C6	O7	1.4135(12)
C3A	C4	1.4411(14)	C6	C16	1.4308(14)
C3A	C7A	1.4017(14)	O7	C7A	1.3387(12)

and

Table 2. Selected bond angles [°] for compound 5.

Atom	Atom	Atom	Angle/°	Atom	Atom	Atom	Angle/°
C7A	N1	N2	102.23(8)	O14	C4	C5	120.99(10)
C3	N2	N1	113.26(8)	C6	C5	C4	119.08(9)
C8	N2	N1	119.35(8)	O15	C5	C4	116.91(9)
C8	N2	C3	127.39(9)	O15	C5	C6	124.01(10)
C3A	C3	N2	106.46(9)	O7	C6	C5	123.66(9)
C4	C3A	C3	134.37(10)	C16	C6	C5	125.60(10)
C7A	C3A	C3	104.07(9)	C16	C6	O7	110.74(9)
C7A	C3A	C4	121.56(9)	C7A	O7	C6	116.70(8)
C5	C4	C3A	113.86(9)	C3A	C7A	N1	113.97(9)
O14	C4	C3A	125.15(10)	O7	C7A	N1	120.98(9)

. The C=O bond length of the pyran-4-one moiety is 1.2265(14) Å which is characteristic of ketone [60]. The C(5)–O(15) bond length [1.2723(13) Å] is shorter than the typical C–O single bond (~1.43 Å) [61], but longer than the typical C=O double bond (~1.23 Å) [62]. It is notable that the C(6)-O(7) bond length [1.4135(12) Å] is longer than that in the O(7)–C(7a) [1.3387(12) Å]. The N(1)–N(2) and N(2)–C(3) bond lengths are 1.3839(12) and 1.3458(14) Å, respectively, and agree with the known bond lengths of pyrazole compounds [63,64,65,66]. The sum of the angles between the covalent bonds around the N(2) atom is 360°, which indicates that a trigonal planar geometry exists at the sp²-hybridized nitrogen atom. The molecules in the crystal are located in columns made up of asymmetric units held by hydrogen bonds (Figure 5b).

2.4. Optical Investigations

The optical properties of 5-hydroxy-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-ones 3a–h in various solvents, such as polar protic (MeOH), polar aprotic (THF and DMF), and non-polar (toluene), were investigated by UV–vis spectroscopy; the compounds were also subjected to fluorimetric measurements. The UV–vis electronic absorption spectra of compounds 3a and 3b in MeOH showed the absorption maximum in the 337 and 341 nm, respectively (Figure 6a,

Table 3. Absorption (λ_abs of the absorption maxima and ε), fluorescence emission (λ^N*_em, λ^T*_em, ratio I_N*/I_T* and quantum yield Φ_f) parameters, and Stokes shifts for 3a–h in MeOH (^∗λ_ex = 380 nm); sh = shoulder.

Entry	Comp.	λabs (nm)	ε × 103 (dm3 mol−1 cm−1)	λN*em (nm)	λT*em (nm)	IN*/IT*	Stokes Shift (cm−1)	Φf (%)
1	3a	337sh 311	70.89 78.45	482	582	0.102	8927 12491	59.3
2	3b	341sh 317	112.50 119.51	428	586	0.009	5961 12261	42.7
3	3c	355 320sh 240	93.74 66.27 54.91	446	582	0.161	5747 10987	13.4
4	3d	361 311 261	43.82 34.60 23.65	479	580	0.406	6824 10459	52.7
5	3e	353 321sh 310sh 293 245sh	70.76 60.39 57.42 56.73 55.59	435	591	0.043	5340 11408	76.1
6	3f	365 317sh 266	80.34 59.96 41.23	438	582	0.046	4566 10215	55.8
7	3g	360 317 260	138.88 116.75 53.16	435	575	0.054	4789 10386	42.6
8	3h	355sh 329	49.99 61.54	493	611	0.031	7885 11802	13.1

, entries 1, 2). The presence of electron-donating substituents on the phenyl ring of compounds 3c,d resulted in a bathochromic shift of the longest wavelength absorption transition. The presence of the 4-methoxyphenyl substituent of structure 3c shifted λ_max upward by 18 nm (Table 3, entry 3), and the presence of the 3,4-dimethoxyphenyl substituent in structure 3d shifted λ_max upward by 24 nm (Table 3, entry 4) compared to 3a, respectively. The bathochromic effect of λ_max at 353 nm is also observed in the UV spectra of the naphthalene ring containing compound 3e, with a significant delocalization of 10-π electrons (Table 3, entry 5). Moreover, the replacement of the phenyl ring in the molecular structure of the products by heterocyclic rings, thiophen-2-yl, furan-3-yl, and pyridin-4-yl moieties induced a significant bathochromic shift of the near-ultraviolet band compared to that of compound 3a. Specifically, the spectra of the compounds 3f, 3g, and 3h contained intense absorption bands with λ_max at 365, 360 and 355 nm, respectively (Table 3, entries 6, 7, 8).

The fluorescence spectra of compounds 3a–h in the MeOH solution contained two well-separated fluorescence bands at around 440 and 590 nm (Figure 6b, Table 3). It is well known that the fluorescence spectra of 3-hydroxyflavone exhibit double emission due to excited-state intramolecular proton transfer (ESIPT) [67,68,69,70,71,72,73,74,75]. Similarly, in compounds 3a–h, the proton transfer process (ESIPT) can occur, resulting in the formation of two forms in the excited state: the normal (N*) and tautomeric (ESIPT product, T*) forms. For example, the excitation of form N-3a leads to the excited state N*, which passes into the product T* by means of proton transfer (Figure 7). The T* form then relaxes to the ground state T form and emits fluorescence at a much longer wavelength compared to normal absorption [28,44]. Therefore, the form N* of the normal emission has a Stokes shift of 8927 cm⁻¹, while the tautomeric product T* has a Stokes shift of 12491 cm⁻¹.

Measurements of the intensity ratio of the N* and T* bands, I_N*/I_T*, in ESIPT compounds are used for ratiometric detection [70]. A strong effect of group substitution in the compounds 3a–h was observed on the I_N*/I_T* fluorescence intensity ratio. 4-Chlorophenyl-substituted compound 3b, compared to the corresponding unsubstituted compound 3a, showed a dramatically decreased I_N*/I_T ratio of ~11-fold (Table 3, entry 2). Conversely, the 4-methoxyphenyl-substituted compound 3c and 3,4-dimethoxyphenyl-substituted compound 3d, compared to the corresponding compound 3a, showed increased I_N*/I_T* ratios by ~1.6- and ~4-fold, respectively (Table 3, entries 3,4). In addition, it was found that the corresponding compounds 3e–h, containing the naphthalen-2-yl, thiophen-2-yl, furan-3-yl, and pyridin-4-yl groups replacing the phenyl group in compound 3a, caused a decrease in I_N*/I_T* ratios of ~2–3-fold (Table 3, entries 5–8).

The fluorescence quantum yield (Φ_f) of the solutions was estimated using the integrating sphere method. It appeared that the fluorescence quantum yield was sensitive to the structure of compounds 3a–h. For unsubstituted compound 3a, a high Φ_f value was observed at 59.3%. The fluorescence quantum yield of 4-methoxyphenyl-group-containing compound 3c was low and did not exceed 14%. The highest Φ_f value (76.1%) was measured for naphthalen-2-yl-group-containing compound 3e; the thiophen-2-yl, furan-3-yl, and pyridin-4-yl groups of compounds 3f, 3g, and 3h emitted fluorescence with the observed Φ_f values of 55.8%, 42.6%, and 13.1%, respectively. It is notable that 3-hydroxyflavone had low quantum yield values in methanol (Φ_f = 3%) and DMF (Φ_f = 1.3%) [70].

Next, the UV–vis electronic absorption spectra of compounds 3a–h in a polar aprotic solvent, THF, showed the absorption maximum in the 339–362 nm range (Figure 8a,

Table 4. Absorption (λ_abs absorption maxima and ε), fluorescence emission (λ^N*_em, λ^T*_em, ratio I_N*/I_T*, and quantum yield Φ_f) parameters, and Stokes shifts for 3a–h in aprotic solvents (^a THF, ^b DMF, and ^c toluene) (^*λ_ex = 380 nm); sh = shoulder.

Entry	Comp.	λabs (nm)	ε × 103 (dm3 mol−1 cm−1)	λN*em (nm)	λT*em (nm)	IN*/IT*	Stokes Shift (cm−1)	Φf (%)
1	3aa	339sh 315	58.67 69.15	466	588	0.014	8039 12492	59.2
2	3ba	339 317 240	49.24 53.74 22.77	428	590	0.019	6134 6134	75.5
3	3ca	353 318sh 260	69.71 52.84 30.30	428	591	0.005	4964 11408	19.2
4	3da	362 311 268	58.61 44.19 23.99	429	594	0.006	4314 10789	39.6
5	3ea	352 334sh 295 283	63.18 59.61 46.02 45.73	416	598	0.012	4371 11687	50.6
6	3fa	357 327sh 266	35.90 28.75 15.87	423	593	0.023	43,701 11148	41.2
7	3ga	352 317 262	82.58 75.99 32.57	421	584	0.020	4656 11286	55.0
8	3ha	351sh 335sh 319	40.75 57.39 64.62	442	610	0.221	5866 12097	30.1
9	3ab	338sh 315	64.22 75.82	428	589	0.009	6221 12608	45.5
10	3ac	357sh 338 322	43.31 57.48 62.27	430	581	0.004	4755 10800	67.7

, entries 1–8). The fluorescence spectra (*λ_ex = 380 nm) of compounds 3a–h in the THF solution showed two fluorescence bands at around 441 nm and 591 nm (Figure 8b, Table 4, entries 1–8), which were similar to the bands in MeOH. The inhibition of the ESIPT reaction by protic solvents in 3-hydroxyflavones is associated with the formation of intermolecular H-bonds, which weaken the intramolecular H-bond necessary for the ESIPT reaction [69,74]. Therefore, the relative intensity of the N* band was very weak compared to that of the T* band for compounds 3a in THF as an aprotic solvent. Compounds 3c–g, especially the ones containing methoxyphenyl groups, presented dramatically decreased I_N*/I_T* ratios in the THF solutions compared to those in MeOH, but the 4-chlorophenyl substituent possessing compound 3b retained similar I_N*/I_T* ratios. However, compound 3h containing the pyridinyl substituent possessed reversed I_N*/I_T* ratios of 0.221 from 0.031 in MeOH. It is possible that the molecule transfered the corresponding proton to pyridine instead of to the carbonyl group. In this case, the pyridin-4-yl substituent inhibits the proton transfer process (ESIPT).

The fluorescence spectra of compound 3a in polar aprotic solvent, DMF, contained two fluorescence bands in the regions of 428 and 589 nm and showed an I_N*/I_T* ratio of 0.009 (Figure 8b, Table 4, entry 9), while compound 3a in toluene contained two fluorescence bands in the region of 430 and 589 nm and showed an I_N*/I_T* ratio of 0.004 (Figure 8b, Table 4, entry 10).

Derivative 4 with the 5-MeO substituent had an electron spectrum very close to its analog 3a (absorption maximum 306 nm and 302 nm, respectively) (Figure S1a). In the fluorescence spectrum of compound 4 in THF solution, two bands were observed at 475 and 582 nm with insignificant fluorescence (Φ_f < 0.1%) (Figure S1b, Table S12, entry 1). Ormson et al. reported that the fluorescence quantum yield for 3-hydroxyflavone is much greater than for the corresponding methoxy compounds and their fluorescence lifetimes are longer [76].

The UV–vis absorption and fluorescence emission spectra of 5-substituted 2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-ones 8a,f,g in THF were also investigated (Figure S1a, Table S12). The absorption maximum of compounds 8a,f,g was in the range from 297 to 302 nm (near-ultraviolet region). None of the investigated compounds 8a,f,g exhibited an absorption in the visible portion of the electronic spectrum. Upon excitation at 340 nm in THF solution, compounds 8a,f,g showed fluorescence emission maxima (λ_em) at around 593–603 nm, although fluorescence was weak (Figure S1b, Table S12). Compound 8a derived from 2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one containing 5-phenyl substituent produced a low quantum yield (Φ_f = 1%) (Table S12, entry 2); for compounds 8f and 8g, the observed Φ_f had a negligible value of only <0.1% (Table S12, entries 3, 4). All compounds 8a,f,g possessed very high values of Stokes shift of ~Δυ = 16000 nm.

Finally, we investigated the UV–vis spectra of compounds 5 and 6. In a polar aprotic solvent, THF, both compounds showed the same absorption maximum in the 528 nm (Figure 9,

Table 5. Absorption (λ_abs absorption maxima and ε) of compounds 5 and 6 in THF.

Entry	Comp.	λabs (nm)	ε × 103 (dm3 mol−1 cm−1)
1	5	528	0.55
		499	0.48
		346	0.39
		299	0.42
		261	0.30
2	6	528	0.54
		499	0.49
		348	0.52
		297	0.49
		261	0.37

). The versatility of derivatives of zwitterionic chromophore, including pyran compounds, in synthetic and material applications, has been well documented [77,78,79].

3. Materials and Methods

3.1. General

All the chemicals and solvents were purchased from common commercial suppliers. Diffraction data were collected on a Rigaku, XtaLAB Synergy, Dualflex, HyPix diffractometer (Rigaku Corporation, Tokyo, Japan). The crystals were kept at 150.0(1) K while collecting the data. Using Olex2, the structure was solved with the ShelXT structure solution program using intrinsic phasing and refined with the olex2.refine refinement package using Gauss–Newton minimization. The ¹H, ¹³C, and ¹⁵N NMR spectra were recorded in CDCl₃ or DMSO-d₆ at 25 °C on a Bruker Avance III 700 (700 MHz for ¹H, 176 MHz for ¹³C, and 71 MHz for ¹⁵N) spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) equipped with a 5 mm TCI ¹H-¹³C/¹⁵N/D z-gradient cryoprobe. The chemical shifts were referenced to tetramethylsilane (TMS) and expressed in ppm. The ¹⁵N NMR spectra were referenced against neat, external nitromethane (coaxial capillary). ¹⁹F NMR spectrum (376 MHz) was obtained on a Bruker Avance III 400 instrument (Bruker BioSpin AG, Faellanden, Switzerland) with absolute referencing via δ ratio. The FT-IR spectra were recorded by ATR method on either a Bruker Vertex 70v spectrometer (Bruker Optik GmbH, Ettlingen, Germany) with an integrated Platinum ATR accessory or on a Bruker Tensor 27 spectrometer (Bruker Optik GmbH, Ettlingen, Germany) using KBr pellets. The melting points of the crystalline compounds were measured in open capillary tubes with a Buchi M 565 apparatus and are uncorrected. Mass spectra were obtained using a Shimadzu LCMS-2020 (ESI⁺) spectrometer (Shimadzu Corporation, Kyoto, Japan). High-resolution mass spectra (HRMS) were measured using a Bruker MicrOTOF-Q III (ESI⁺) apparatus (Bruker Daltonik GmbH, Bremen, Germany). All the reactions were performed in oven-dried glassware with magnetic stirring. The reaction progress was monitored by TLC analysis on Macherey-Nagel™ ALUGRAM^® Xtra SIL G/UV254 plates (Macherey-Nagel GmbH & Co. KG, Düren, Germany) which were visualized by UV light (254 and 365 nm wavelengths). The compounds were purified by flash chromatography in glass columns (stationary phase of silica gel, high-purity grade of 9385, pore size of 60 Å, and particle size of 230–400 mesh, supplied by Sigma-Aldrich; Merck KGaA, Darmstadt, Germany). The UV–vis spectra were recorded on a Shimadzu 2600 UV/vis spectrometer (Shimadzu Corporation, Japan). The fluorescence spectra were recorded on an FL920 fluorescence spectrometer from Edinburgh Instruments (Edinburgh Analytical Instruments Limited, Edinburgh, UK). The PL quantum yields were determined from dilute solutions by an absolute method using the Edinburgh Instruments integrating sphere excited with a Xe lamp. The optical densities of the sample solutions were ensured to be below 0.1 to avoid reabsorption effects. All the optical measurements were performed at room temperature under ambient conditions. The following abbreviations are used in reporting the NMR data: Ph, phenyl; Pyr, pyridine; Pz, pyrazole; Naph, naphtalene; and Th, thiophene. The ¹H, ¹³C, and ¹H-¹⁵N HMBC NMR spectra, as well as the HRMS data of the new compounds, are provided in Figures S2–S81 of the Supplementary Material. Crystallographic data have been deposited at the Cambridge Crystallographic Data Centre with CCDC reference number 2287991 for 6-(1-methylpyridin-1-ium-4-yl)-4-oxo-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-5-olate (5); formula C₁₉H₁₇N₃O₄; unit cell parameters: a 10.39395(17) b 12.15508(19) c 13.08074(18), space group P21/c.

3.2. Synthetic Procedures

Compounds 2a–c and 2e–h were synthesized in accordance with the procedure described in ref. [44].

3.2.1. (2E)-3-(3,4-Dimethoxyphenyl)-1-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-one (2d)

The compound was synthesized in accordance with the procedure described in ref. [44] using 3,4-dimethoxybenzaldehyde. Orange solid. Yield 67% (2349 mg); m.p. 225–226 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 3.82 (s, 3H, 4-OCH₃), 3.84 (s, 3H, 3-OCH₃), 7.05 (d, J = 8.1 Hz, 1H, CPh 5-H), 7.33 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.34–7.37 (m, 2H, CPh 2,6-H), 7.52 (t, J = 7.9 Hz, 2H, NPh 3,5-H), 7.57 (d, J = 15.6 Hz, 1H, C(O)CHCH), 7.66 (d, J = 15.6 Hz, 1H, C(O)CHCH), 7.84 (d, J = 7.8 Hz, 2H, NPh 2,6-H), 9.12 (s, 1H, Pz 5-H), 11.07 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 55.6 (4-OCH₃), 55.7 (3-OCH₃), 111.0 (Pz C-4), 111.3 (CPh C-2), 111.8 (CPh C-5), 118.1 (NPh C-2,6), 121.8 (C(O)CHCH), 122.7 (CPh C-6), 126.6 (NPh C-4), 127.5 (CPh C-1), 129.6 (NPh C-3,5), 131.5 (Pz C-5), 138.9 (NPh C-1), 142.0 (C(O)CHCH), 149.0 (CPh C-3), 151.1 (CPh C-4), 162.0 (Pz C-3), 182.9 (C=O). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −182.3 (Pz N-1), −118.3 (Pz N-2). IR (ν_max, cm⁻¹): 3118, 2932, 1652 (C=O), 1586, 1510, 1451, 1218, 1026, 977, 742, 679. HRMS (ESI⁺) for C₂₀H₁₈N₂NaO₄ ([M + Na]⁺) calcd 373.1159, found 373.1162.

3.2.2. General Procedure for the Synthesis of 3a–h

To a solution of 2a–h (1 mmol) in EtOH (5 mL) at −10 °C, aq. NaOH (20%, 1 mL, 5 mmol) was added; the reaction mixture was cooled down to −25 °C and H₂O₂ 30% (0.51 mL, 5 mmol) was added dropwise. The reaction mixture was stirred for 2 h and at room temperature for another 16 h. The solids were filtered off, washed with warm water, cold MeOH, and ether, and dried. The product was recrystallized from ACN.

• 5-Hydroxy-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (3a). Off white solid; yield 58% (177 mg); m.p. 183–184 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 7.46 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.49 (t, J = 7.4 Hz, 1H, 6-CPh 4-H), 7.55–7.58 (m, 2H, 6-CPh 3,5-H), 7.58–7.61 (m, 2H, NPh 3,5-H), 8.01–8.03 (m, 2H, NPh 2,6-H), 8.13–8.14 (m, 2H, 6-CPh 2,6-H), 9.38 (s, 1H, 3-H), 9.44 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 108.3 (C-3a), 119.9 (NPh C-2,6), 126.6 (C-3), 127.9 (6-CPh C-2,6), 128.5 (NPh C-4), 129.0 (6-CPh C-3,5), 130.0 (6-CPh C-4), 130.2 (NPh C-3,5), 131.8 (6-CPh C-1), 139.16 (C-5), 139.19 (NPh C-1), 144.4 (C-6), 161.2 (C-7a), 171.8 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −167.7 (N-2), −117.0 (N-1). IR (ν_max, cm⁻¹): 3110, 3062, 2920, 2850, 1679 (C=O), 1568, 1489, 1199, 1110, 913, 832, 761, 696. HRMS (ESI⁺) for C₁₈H₁₂N₂NaO₃ ([M + Na]⁺) calcd 327.0740, found 327.0740.
• 6-(4-Chlorophenyl)-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one (3b). Light yellow solid; yield 63% (213 mg); m.p. 262–263 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 7.45 (t, J = 7.3 Hz, 1H, NPh 4-H), 7.58 (t, J = 7.8 Hz, 2H, NPh 3,5-H), 7.62 (d, J = 8.6 Hz, 2H, 6-CPh 3,5-H), 8.01 (d, J = 7.9 Hz, 2H, NPh 2,6-H), 8.15 (d, J = 8.6 Hz, 2H, 6-CPh 2,6-H), 9.38 (s, 1H, 3-H), 9.70 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 107.9 (C-3a), 119.5 (NPh C-2,6), 126.3 (C-3), 128.1 (NPh C-4), 128.6 (6-CPh C-3,5), 129.1 (6-CPh C-2,6), 129.8 (NPh C-3,5), 130.2 (6-CPh C-1), 134.1 (6-CPh C-4), 138.7 (NPh C-1), 139.1 (C-5), 142.7 (C-6), 160.6 (C-7a), 171.3 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −167.5 (N-2), −117.2 (N-1). IR (ν_max, cm⁻¹): 3348, 3289, 3100, 1645 (C=O), 1576, 1495, 1442, 1098, 825, 752, 679. HRMS (ESI⁺) for C₁₈H₁₁ClN₂NaO₃ ([M + Na]⁺) calcd 361.0350, found 361.0350.
• 5-Hydroxy-6-(4-methoxyphenyl)-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one (3c). Yellow solid; yield 51% (171 mg); m.p. 263–264 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 3.85 (s, 3H, CH₃), 7.12–7.13 (m, 2H, 6-CPh 3,5-H), 7.45 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.57–7.60 (m, 2H, NPh 3,5-H), 8.00–8.02 (m, 2H, NPh 2,6-H), 8.09–8.12 (m, 2H, 6-CPh 2,6-H), 9.27 (s, 1H, 3-H), 9.36 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 55.3 (CH₃), 107.9 (C-3a), 114.2 (6-CPh C-3,5), 119.4 (NPh C-2,6), 123.6 (6-CPh C-1), 126.0 (C-3), 128.0 (NPh C-4), 129.2 (6-CPh C-2,6), 129.8 (NPh C-3,5), 137.8 (C-5), 138.8 (NPh C-1), 144.4 (C-6), 160.2 (6-CPh C-4), 160.7 (C-7a), 171.2 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −168.3 (N-2). IR (ν_max, cm⁻¹): 3286, 3134, 1642 (C=O), 1580, 1509, 1441, 1256, 1108, 821, 748, 680. HRMS (ESI⁺) for C₁₉H₁₄N₂NaO₄ ([M + Na]⁺) calcd 357.0846, found 357.0841.
• 6-(3,4-Dimethoxyphenyl)-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one (3d). Orange solid; yield 67% (245 mg); m.p. 252–253 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 3.84 (s, 3H, 6-CPh 3-OCH₃), 3.85 (s, 3H, 6-CPh 4-OCH₃), 7.15 (d, J = 8.7 Hz, 1H, 6-CPh 5-H), 7.45 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.58 (t, J = 8.0 Hz, 2H, NPh 3,5-H), 7.71 (d, J = 2.1 Hz, 1H, 6-CPh 2-H), 7.78 (dd, J = 8.6, 2.1 Hz, 1H, 6-CPh 6-H), 8.02 (d, J = 7.7 Hz, 2H, NPh 2,6-H), 9.28 (s, 1H, OH), 9.35 (s, 1H, 3-H). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 55.6 (6-CPh 3,4-OCH₃), 107.8 (C-3a), 110.7 (6-CPh C-2), 111.5 (6-CPh C-5), 119.4 (NPh C-2,6), 121.3 (6-CPh C-6), 123.7 (6-CPh C-1), 126.0 (C-3), 128.0 (NPh C-4), 129.8 (NPh C-3,5), 137.9 (C-5), 138.8 (NPh C-1), 144.3 (C-6), 148.3 (6-CPh C-3), 150.0 (6-CPh C-4), 160.6 (C-7a), 171.1 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −168.2 (N-2), −117.3 (N-1). IR (ν_max, cm⁻¹): 3281, 2963, 1632 (C=O), 1583, 1515, 1439, 1106, 754, 657. HRMS (ESI⁺) for C₂₀H₁₆N₂NaO₅ ([M + Na]⁺) calcd 387.0951, found 387.0953.
• 5-Hydroxy-6-(naphthalen-2-yl)-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one (3e). Yellow solid; yield 32% (113 mg); m.p. 256–257 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 7.46 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.59–7.63 (m, 4H, NPh 3,5-H and Naph 6,7-H), 7.99 (d, J = 7.8 Hz, 1H, Naph 5-H), 8.04 (d, J = 7.9 Hz, 2H, NPh 2,6-H), 8.06–8.09 (m, 1H, Naph 4-H), 8.09–8.10 (m, 1H, Naph 8-H), 8.27 (dd, J = 8.7, 1.8 Hz, 1H, Naph 3-H), 8.71 (s, 1H, Naph 1-H), 9.41 (s, 1H, 3-H), 9.59 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 107.8 (C-3a), 119.3 (NPh C-2,6), 124.3 (Naph C-3), 126.1 (C-3), 126.7 (Naph C-7), 127.38 (Naph C-1 and Naph C-6), 127.44 (Naph C-5), 127.82 (Naph C-4), 128.01 (NPh C-4), 128.76 (Naph C-8), 128.79 (Naph C-2), 129.7 (NPh C-3,5), 132.4 (Naph C-8a), 132.9 (Naph C-4a), 138.7 (NPh C-1), 139.0 (C-5), 143.8 (C-6), 160.7 (C-7a), 171.2 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −167.7 (N-2), −117.4 (N-1). IR (ν_max, cm⁻¹): 3240, 1629 (C=O), 1576, 1564, 1441, 1386, 1216, 1096, 753, 685. HRMS (ESI⁺) for C₂₂H₁₄N₂NaO₃ ([M + Na]⁺) calcd 377.0897, found 377.0908.
• 5-Hydroxy-2-phenyl-6-(thiophen-2-yl)pyrano[2,3-c]pyrazol-4(2H)-one (3f). Yellow solid; yield 62% (193 mg); m.p. 187–188 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 7.29 (dd, J = 5.0, 3.8 Hz, 1H, Th 5-H), 7.44–7.46 (m, 1H, NPh 4-H), 7.57–7.60 (m, 2H, NPh 3,5-H), 7.87 (dd, J = 3.8, 1.2 Hz, 1H, Th 3-H), 7.88 (dd, J = 5.0, 1.2 Hz, 1H, Th 4-H), 8.00–8.02 (m, 2H, NPh 2,6-H), 9.35 (s, 1H, 3-H), 10.12 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 108.1 (C-3a), 119.3 (NPh C-2,6), 126.1 (C-3), 127.66 (Th C-3), 127.70 (Th C-5), 127.9 (NPh C-4), 129.6 (NPh C-3,5), 130.4 (Th C-4), 132.3 (Th C-2), 136.5 (C-5), 138.6 (NPh C-1), 141.9 (C-6), 160.2 (C-7a), 170.4 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −168.6 (N-2), −117.2 (N-1). IR (ν_max, cm⁻¹): 3259, 3113, 1629 (C=O), 1575, 1503, 1217, 1103, 826, 753, 685. HRMS (ESI⁺) for C₁₆H₁₀N₂NaO₃S ([M + Na]⁺) calcd 333.0304, found 333.0309.
• 6-(Furan-3-yl)-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one (3g). Beige solid; yield 30% (89 mg); m.p. 228–229 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 6.78 (dd, J = 3.4, 1.7 Hz, 1H, Furanyl 5-H), 7.23 (d, J = 3.4 Hz, 1H, Furanyl 4-H), 7.45 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.59 (t, J = 7.9 Hz, 2H, NPh 3,5-H), 8.00 (d, J = 7.8 Hz, 2H, NPh 2,6-H), 8.02 (d, J = 1.0 Hz, 1H, Furanyl 2-H), 9.36 (s, 1H, 3-H), 9.86 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 108.2 (C-3a), 112.7 (Furanyl C-5), 114.5 (Furanyl C-4), 119.3 (NPh C-2,6), 126.1 (C-3), 127.9 (NPh C-4), 129.7 (NPh C-3,5), 136.9 (C-5), 138.0 (Furanyl C-3), 138.6 (NPh C-1), 144.0 (C-6), 144.9 (Furanyl C-2), 160.2 (C-7a), 170.3 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −168.4 (N-2), −117.1 (N-1). IR (ν_max, cm⁻¹): 3246, 3138, 2957, 2856, 1633 (C=O), 1576, 1483, 1221, 1124, 934, 845, 755, 681. HRMS (ESI⁺) for C₁₆H₁₀N₂NaO₄ ([M + Na]⁺) calcd 317.0533, found 317.0534.
• 5-Hydroxy-2-phenyl-6-(pyridin-4-yl)pyrano[2,3-c]pyrazol-4(2H)-one (3h). Yellow solid; yield 53% (163 mg); m.p. 298–299 °C. ¹H NMR (700 MHz, DMSO-d₆) δ 7.45–7.48 (m, 1H, Ph 4-H), 7.56–7.61 (m, 2H, Ph 3,5-H), 8.00–8.03 (m, 2H, Ph 2,6-H), 8.04–8.07 (m, 2H, Pyr 3,5-H), 8.74–8.77 (m, 2H, Pyr 2,4-H), 9.41 (s, 1H, 3-H), 10.13 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆) δ 107.8 (C-3a), 119.4 (Ph C-2,6), 120.6 (Pyr C-3,5), 126.4 (C-3), 128.1 (Ph C-4), 129.7 (Ph C-3,5), 138.45 (Pyr C-4), 138.53 (Ph C-1), 140.5 (C-6), 140.9 (C-5), 150.0 (Pyr C-2,6), 160.5 (C-7a), 171.2 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −166.9 (N-2), −117.1 (N-1), −62.2 (Pyr N). IR (ν_max, cm⁻¹): 3112, 3087, 1648 (C=O), 1571, 1500, 1442, 1228, 1026, 834, 754, 629. HRMS (ESI⁺) for C₁₇H₁₁N₃O₃ ([M + H]⁺) calcd 306.0873, found 306.0871.

3.2.3. Procedure for the Synthesis of 5-Methoxy-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (4)

To a solution of 3a (304 mg, 1 mmol) in dioxane (30 mL) Cs₂CO₃, (0.65 g, 2 mmol) and MeI (0.07 mL, 1.1 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h, neutralized with aq. KHSO₄, and purified via column chromatography (SiO₂, eluent: methanol/dichloromethane, 1:9, v/v). White solid; yield 79% (251 mg); m.p. 220–221 °C. ¹H NMR (700 MHz, DMSO-d₆): δ_H ppm 3.77 (s, 3H, CH₃), 7.45 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.56–7.61 (m, 5H, NPh 3,5-H and 6-CPh 3,4,5-H), 7.96–7.98 (m, 2H, 6-CPh 2,6-H), 8.00 (d, J = 8.0 Hz, 2H, NPh 2,6-H), 9.34 (s, 1H, 3-H). ¹³C NMR (176 MHz, DMSO-d₆): δ_C ppm 60.1 (CH₃), 109.8 (C-3a), 119.5 (NPh C-2,6), 126.5 (C-3), 128.1 (NPh C-4), 128.2 (6-CPh C-2,6), 128.7 (6-CPh C-3,5), 129.8 (NPh C-3,5), 130.4 (6-CPh C-1), 130.7 (6-CPh C-4), 138.7 (NPh C-1), 140.8 (C-5), 154.1 (C-6), 160.8 (C-7a), 172.1 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −168.0 (N-2), −115.9 (N-1). IR (ν_max, cm⁻¹): 3101, 2936, 1640 (C=O), 1578, 1554, 1443, 1351, 1134, 764, 753, 682. HRMS (ESI⁺) for C₁₉H₁₄N₂NaO₃ ([M + Na]⁺) calcd 341.0897, found 341.0899.

3.2.4. Procedure for the Synthesis of 6-(1-Methylpyridin-1-ium-4-yl)-4-oxo-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-5-olate (5)

To a solution of 3a (304 mg, 1 mmol) in dioxane (30 mL), Cs₂CO₃ (0.65 g, 2 mmol) and MeI (0.07 mL, 1.1 mmol) were added. The reaction mixture was stirred at 40 °C for 3 h, neutralized with aq. KHSO₄, and purified via column chromatography (SiO₂, eluent: methanol/dichloromethane, 1:9, v/v). Red solid; yield 59% (264 mg); decomposition 240–241 °C. ¹H NMR (700 MHz, DMSO-d₆) δ 3.95 (CH₃), 7.42 (m, 1H, Ph 4-H), 7.56 (m, 2H, Ph 3,5-H), 7.98 (m, 2H, Ph 2,6-H), 8.12–8.20 (m, 2H, Pyr 2,6-H), 9.14–9.20 (m, 2H, Pyr 3,5-H), 9.41 (s, 1H, 3-H). ¹³C NMR (176 MHz, DMSO-d₆) δ 44.5 (CH₃), 109.4 (C-3a), 112.9 (Pyr C-5), 114.6 (Pyr C-3), 119.1 (Ph C-2,6), 126.7 (C-3), 127.6 (Ph C-4), 129.6 (Ph C-3,5), 134.8 (C-6), 138.7 (Ph C-1), 140.9 (Pyr C-6), 141.6 (Pyr C-2), 143.3 (Pyr C-4), 161.2 (C-7a), 164.1 (C-5), 176.1 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −214.4 (Pyr N); −170.1 (N-2), −120.2 (N-1). IR (ν_max, cm⁻¹): 3089, 2920, 2852, 1629 (C=O), 1569, 1488, 1465, 1382, 1189, 756, 689. HRMS (ESI⁺) for C₁₈H₁₄N₃O₃ ([M + Na]⁺) calcd 342.0849, found 342.0852.

3.2.5. Procedure for the Synthesis of 4-(5-Hydroxy-4-oxo-2-phenyl-2,4-dihydropyrano[2,3-c]pyrazol-6-yl)-1-methylpyridin-1-ium Iodide (6)

To a solution of 3a (305 mg, 1 mmol) in ACN (15 mL), MeI (1 mL, 16.1 mmol) was added. The reaction mixture was stirred at 40 °C for 2 h and diluted with DMF (15 mL); the solution was slowly dripped into cold diethyl ether. The formed crystals were filtrated and washed with a small amount of MeOH and diethyl ether. Orange solid; yield 78% (348 mg); decomposition 277–278 °C. ¹H NMR (700 MHz, DMSO-d₆) δ 4.39 (CH₃), 7.47 (m, 1H, Ph 4-H), 7.58 (m, 2H, Ph 3,5-H), 7.97 (m, 2H, Ph 2,6-H), 8.63 (m, 2H, Pyr 3,5-H), 9.03 (m, 2H, Pyr 2,6-H), 9.45 (s, 1H, 3-H), 11.49 (s, 1H, OH). ¹³C NMR (176 MHz, DMSO-d₆) δ 48.0 (CH₃), 108.4 (C-3a), 119.9 (Ph C-2,6), 123.8 (Pyr C-3,5), 127.4 (C-3), 128.9 (Ph C-4), 130.3 (Ph C-3,5), 146.1 (Pyr C-4), 138.8 (Ph C-1), 137.5 (C-6), 145.4 (C-5), 145.9 (Pyr C-2,6), 160.7 (C-7a), 171.4 (C-4). ¹⁵N NMR (71 MHz, DMSO-d₆): δ_N ppm −183.2 (Pyr N); −165.7 (N-2), −117.1 (N-1). IR (ν_max, cm⁻¹): 3135, 3066, 1646 (C=O), 1575, 1497, 1441, 1388, 1232, 1197, 1109, 761. HRMS (ESI⁺) for C₁₈H₁₄N₃O₃ (M⁺) calcd 320.1030, found 320.1032.

3.2.6. Procedure for the Synthesis of 4-Oxo-2,6-diphenyl-2,4-dihydropyrano[2,3-c]pyrazol-5-yl Trifluoromethanesulfonate (7)

To a solution of 3a (304 mg, 1 mmol) in DCM (30 mL), at 0 °C, TEA (0.7 mL, 5 mmol) and Tf₂O (0.34 mL, 2 mmol) were added dropwise. The reaction mixture was stirred at 24 °C for 16 h, diluted with DCM (100 mL), washed with brine (100 mL), and purified via column chromatography (SiO₂, eluent: ethyl acetate/n-hexane, 1:6, v/v). Beige solid; yield 74% (323 mg); m.p. 200–201 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 7.46 (t, J = 7.3 Hz, 1H, NPh 4-H), 7.55–7.58 (m, 4H, NPh 3,5-H and 6-CPh 3,5-H), 7.62 (t, J = 7.3 Hz, 1H, 6-CPh 4-H), 7.78 (d, J = 8.0 Hz, 2H, NPh 2,6-H), 7.87 (d, J = 7.5 Hz, 2H, 6-CPh 2,6-H), 8.59 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 109.4 (C-3a), 118.2 (q, ¹J_C,F = 320.8 Hz, CF₃), 120.3 (NPh C-2,6), 125.5 (C-3), 128.4 (6-CPh C-1), 129.0 (6-CPh C-3,5), 129.1 (NPh C-4), 129.2 (6-CPh C-2,6), 130.1 (NPh C-3,5), 132.6 (6-CPh C-4), 134.6 (C-5), 138.9 (NPh C-1), 158.2 (C-6), 161.3 (C-7a), 168.8 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −165.8 (N-2), −112.7 (N-1). ¹⁹F NMR (376 MHz, CDCl₃): δ_F ppm –74.0 (CF₃). IR (ν_max, cm⁻¹): 3105, 2918, 1658 (C=O), 1594, 1553, 1425, 1208, 1134, 1019, 897, 757, 686, 600. HRMS (ESI⁺) for C₁₉H₁₁F₃N₂NaO₅S ([M + Na]⁺) calcd 459.0233, found 459.0235.

3.2.7. General Procedure for the Synthesis of 5-(Hetero)aryl-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-ones 8a–e

To a solution of 7 (436 mg, 1 mmol) in dioxane (15 mL), K₃PO₄ (634 mg, 3 mmol), KBr (131 mg, 1.1 mmol), appropriate (hetero)arylboronic acid (2.5 mmol), and Pd(PPh₃)₄ (69 mg, 0.06 mmol) were added. The reaction mixture was stirred at 90 °C for 16 h, diluted with H₂O (80 mL), extracted with DCM (3 × 15 mL), and purified via column chromatography (SiO₂, eluent: ethyl acetate/n-hexane, 1:6, v/v).

• 2,5,6-Triphenylpyrano[2,3-c]pyrazol-4(2H)-one (8a). Yellow solid; yield 95% (346 mg); m.p. 265–266 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 7.20–7.21 (m, 2H, 5-CPh 2,6-H), 7.24–7.25 (m, 2H, 6-CPh 3,5-H), 7.28–7.33 (m, 4H, 5-CPh 3,4,5-H and 6-CPh 4-H), 7.39 (d, J = 7.6 Hz, 2H, 6-CPh 2,6-H), 7.42 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.53 (t, J = 7.9 Hz, 2H, NPh 3,5-H), 7.80 (d, J = 8.0 Hz, 2H, NPh 2,6-H), 8.55 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 109.7 (C-3a), 119.9 (NPh C-2,6), 123.0 (C-5), 124.7 (C-3), 127.7 (5-CPh C-4), 128.0 (6-CPh C-3,5), 128.24 (NPh C-4), 128.29 (5-CPh C-3,5), 129.78 (6-CPh C-2,6), 129.83 (NPh C-3,5), 130.0 (6-CPh C-4), 131.4 (5-CPh C-2,6), 132.8 (5-CPh C-1), 133.0 (6-CPh C-1), 139.2 (NPh C-1), 160.8 (C-6), 162.4 (C-7a), 175.5 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −169.5 (N-2), −115.3 (N-1). IR (ν_max, cm⁻¹): 3093, 2922, 1642 (C=O), 1578, 1561, 1493, 1349, 1224, 1056, 755, 730, 694, 683. HRMS (ESI⁺) for C₂₄H₁₆N₂NaO₂ ([M + Na]⁺) calcd 387.1104, found 387.1107.
• 5-(4-Methylphenyl)-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (8b). White solid; yield 62% (235 mg); m.p. 256–257 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 2.34 (s, 3H, CH₃), 7.08 (m, 2H, 5-CPh 2,6-H), 7.11 (m, 2H, 5-CPh 3,5-H), 7.24–7.27 (m, 2H, 6-CPh 3,5-H), 7.32 (m, 2H, 6-CPh 4-H), 7.40–7.43 (m, 3H, 6-CPh 2,6-H, NPh 4-H), 7.53 (m, 2H, NPh 3,5-H), 7.78–7.81 (m, 2H, NPh 2,6-H), 8.55 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 21.3 (CH₃), 109.7 (C-3a), 119.8 (NPh C-2,6), 122.9 (C-5), 124.6 (C-3), 128.0 (6-CPh C-3,5), 128.2 (NPh C-4), 129.1 (5-CPh C-3,5), 129.6 (5-CPh C-1), 129.7 (6-CPh C-2,6), 129.8 (NPh C-3,5), 129.9 (6-Ph C-4), 131.2 (5-CPh C-2,6), 133.1 (6-CPh C-1), 137.4 (5-CPh C-4), 139.2 (NPh C-1), 160.5 (C-6), 162.3 (C-7a), 175.7 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −169.7 (N-2), −115.3 (N-1). IR (ν_max, cm⁻¹): 3098, 3023, 1649 (C=O), 1578, 1565, 1348, 1181, 1021, 755, 742, 732, 683. HRMS (ESI⁺) for C₂₅H₁₈N₂O₂ ([M + Na]⁺) calcd 401.1260, found 401.1262.
• 5-(4-Methoxyphenyl)-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (8c). White solid; yield 77% (304 mg); m.p. 236–237 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 3.80 (s, 3H, CH₃), 6.85 (m, 2H, 5-CPh 3,5-H), 7.12 (m, 2H, 5-CPh 2,6-H), 7.24–7.28 (m, 2H, 6-CPh 3,5-H), 7.32 (m, 2H, 6-CPh 4-H), 7.40–7.44 (m, 3H, 6-CPh 2,6-H, NPh 4-H), 7.54 (m, 2H, NPh 3,5-H), 7.80 (m, 2H, NPh 2,6-H), 8.54 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 55.2 (CH₃), 109.7 (C-3a), 113.9 (5-CPh C-3,5), 119.8 (NPh C-2,6), 122.5 (C-5), 124.6 (C-3), 124.8 (5-CPh C-1), 128.0 (6-CPh C-3,5), 128.2 (NPh C-4), 129.7 (6-CPh C-2,6), 129.8 (NPh C-3,5), 129.9 (6-Ph C-4), 132.5 (5-CPh C-2,6), 133.2 (6-CPh C-1), 139.2 (NPh C-1), 159.1 (5-CPh C-4), 160.5 (C-6), 162.3 (C-7a), 175.8 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −169.7 (N-2), −115.6 (N-1). IR (ν_max, cm⁻¹): 3102, 3024, 1650 (C=O), 1598, 1567, 1335, 1241, 1167, 1023, 748, 686, 549. HRMS (ESI⁺) for C₂₅H₁₈N₂O₃ ([M + Na]⁺) calcd 417.1210, found 417.1208.
• 5-(4-Chlorophenyl)-2,6-diphenylpyrano[2,3-c]pyrazol-4(2H)-one (8d). White solid; yield 44% (176 mg); m.p. 255–256 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 7.14 (m, 2H, 5-CPh 2,6-H), 7.27–7.31 (m, 4H, 5-CPh 3,5-H, 6-CPh 3,5-H), 7.35 (m, 2H, 6-CPh 4-H), 7.39 (m, 2H, 6-CPh 2,6-H), 7.43 (m, 1H, NPh 4-H), 7.54 (m, 2H, NPh 3,5-H), 7.80 (m, 2H, NPh 2,6-H), 8.55 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 109.5 (C-3a), 119.9 (NPh C-2,6), 121.8 (C-5), 124.7 (C-3), 128.2 (6-CPh C-3,5), 128.4 (NPh C-4), 128.6 (5-CPh C-3,5), 129.7 (6-CPh C-2,6), 129.8 (NPh C-3,5), 130.3 (6-Ph C-4), 131.3 (5-CPh C-1), 132.7 (6-CPh C-1), 132.8 (5-CPh C-2,6), 133.7 (5-CPh C-4), 139.1 (NPh C-1), 161.0 (C-6), 162.32 (C-7a), 175.2 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −169.1 (N-2), −115.0 (N-1). IR (ν_max, cm⁻¹): 3206, 3105, 1650 (C=O), 1568, 1422, 1348, 1211, 1135, 757, 731, 686. HRMS (ESI⁺) for C₂₄H₁₅ClN₂O₂ ([M + Na]⁺) calcd 421.0714, found 421.0711.
• 2,6-Diphenyl-5-(thiophen-3-yl)pyrano[2,3-c]pyrazol-4(2H)-one (8e). Beige solid; yield 80% (297 mg); m.p. 265–266 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 6.88 (m, 1H, Th 4-H), 7.20 (m, 1H, Th 2-H), 7.24 (m, 1H, Th 5-H), 7.31 (m, 2H, 6-CPh 3,5-H), 7.37 (m, 2H, 6-CPh 4-H), 7.42 (m, 1H, NPh 4-H), 7.44 (m, 2H, 6-CPh 2,6-H), 7.54 (m, 2H, NPh 3,5-H), 7.80 (m, 2H, NPh 2,6-H), 8.54 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 109.6 (C-3a), 118.1 (C-5), 119.9 (NPh C-2,6), 124.6 (C-3), 124.7 (Th C-5), 126.4 (Th C-2), 128.1 (6-CPh C-3,5), 128.3 (NPh C-4), 129.8 (Th C-4), 129.5 (6-CPh C-2,6), 129.8 (NPh C-3,5), 130.2 (6-Ph C-4), 131.9 (Th C-3), 132.2 (6-CPh C-1), 139.1 (NPh C-1), 160.8 (C-6), 162.2 (C-7a), 175.3 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −169.4 (N-2), −115.2 (N-1). IR (ν_max, cm⁻¹): 3100, 1644 (C=O), 1577, 1564, 1441, 1328, 1218, 753, 739, 685. HRMS (ESI⁺) for C₂₂H₁₄N₂O₂S ([M + H]⁺) calcd 393.0668, found 393.0669.

3.2.8. Procedure for the Synthesis of tert-Butyl (2E)-3-(4-oxo-2,6-diphenyl-2,4-dihydropyrano[2,3-c]pyrazol-5-yl)prop-2-enoate (8f)

To a solution of 7 (436 mg, 1 mmol) in dry DMF (10 mL), TEA (0.28 mL, 2 mmol), tert-butyl acrylate (0.29 mL, 2 mmol), and Pd(PPh₃)₂Cl₂ (35 mg, 0.05 mmol) were added. The reaction mixture was stirred at 100 °C for 72 h, diluted with H₂O (100 mL), extracted with EtOAc (3 × 50 mL), washed with brine (100 mL), and purified via column chromatography (SiO₂, eluent: dichloromethane). White solid; yield 24% (99 mg); decomposition 312 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 1.48 (s, 9H, C(CH₃)₃), 7.31 (d, J = 15.9 Hz, 1H, CHCHCOOC(CH₃)₃), 7.35 (d, J = 15.8 Hz, 1H, CHCHCOOC(CH₃)₃), 7.42 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.52–7.56 (m, 5H, NPh 3,5-H and 6-CPh 3,4,5-H), 7.68 (d, J = 6.8 Hz, 2H, 6-CPh 2,6-H), 7.79 (d, J = 8.0 Hz, 2H, NPh 2,6-H), 8.54 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 28.2 (C(CH₃)₃), 80.3 (C(CH₃)₃), 110.0 (C-3a), 115.9 (C-5), 120.0 (NPh C-2,6), 125.0 (C-5), 125.5 (CHCHCOOC(CH₃)₃), 128.6 (NPh C-4), 128.8 (6-CPh C-3,5), 130.0 (NPh C-3,5), 130.2 (6-CPh C-2,6), 131.6 (6-CPh C-4), 132.1 (6-CPh C-1), 135.3 (CHCHCOOC(CH₃)₃), 139.2 (NPh C-1), 161.7 (C-7a), 166.0 (C-6), 167.1 (CHCHCOOC(CH₃)₃), 175.2 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −168.8 (N-2), −114.4 (N-1). IR (ν_max, cm⁻¹): 3106, 2971, 1647 (C=O), 1584, 1554, 1445, 1290, 1149, 753, 688. HRMS (ESI⁺) for C₂₅H₂₂N₂NaO₄ ([M + Na]⁺) calcd 437.1472, found 437.1473.

3.2.9. Procedure for the Synthesis of 2,6-Diphenyl-5-(phenylethynyl)pyrano[2,3-c]pyrazol-4(2H)-one (8g)

To a solution of 7 (436 mg, 1 mmol) in dry DMF (10 mL), TEA (0.28 mL, 2 mmol), CuI (19 mg, 0.1 mmol), phenylacetylene (0.16 mL, 1.5 mmol), and Pd(PPh₃)₂Cl₂ (42 mg, 0.06 mmol) were added. The reaction mixture was stirred at 65 °C for 1 h, diluted with H₂O (100 mL), extracted with EtOAc (3 × 50 mL), washed with brine (100 mL), and purified via column chromatography, (SiO₂, eluent: dichloromethane). White solid; yield 71% (276 mg); m.p. 222–223 °C. ¹H NMR (700 MHz, CDCl₃): δ_H ppm 7.31–7.34 (m, 3H, C≡CPh 3,4,5-H), 7.42 (t, J = 7.4 Hz, 1H, NPh 4-H), 7.49–7.50 (m, 2H, C≡CPh 2,6-H), 7.52–7.57 (m, 5H, NPh 3,5-H and 6-CPh 3,4,5-H), 7.79 (d, J = 8.1 Hz, 2H, NPh 2,6-H), 8.25 (d, J = 7.9 Hz, 2H, 6-CPh 2,6-H), 8.55 (s, 1H, 3-H). ¹³C NMR (176 MHz, CDCl₃): δ_C ppm 82.0 (C≡CPh), 97.9 (C≡CPh), 107.7 (C-5), 108.8 (C-3a), 120.0 (NPh C-2,6), 123.3 (C≡CPh C-1), 124.8 (C-3), 128.3 (6-CPh C-3,5), 128.4 (C≡CPh C-3,5), 128.6 (C≡CPh C-4 and NPh C-4), 129.4 (6-CPh C-2,6), 130.0 (NPh C-3,5), 131.66 (6-CPh C-4), 131.71 (C≡CPh C-2,6), 132.3 (6-CPh C-1), 139.1 (NPh C-1), 161.9 (C-7a), 165.1 (C-6), 174.2 (C-4). ¹⁵N NMR (71 MHz, CDCl₃): δ_N ppm −168.6 (N-2), −114.3 (N-1). IR (ν_max, cm⁻¹): 3094, 3057, 1649 (C=O), 1577, 1542, 1442, 1361, 1264, 1118, 750, 684. HRMS (ESI⁺) for C₂₆H₁₆N₂NaO₂ ([M + Na]⁺) calcd 411.1104, found 411.1101.

4. Conclusions

In conclusion, we showed that the diverse 6-aryl-5-hydroxy-2-phenylpyrano[2,3-c]pyrazol-4(2H)-one derivatives as analogues of 3-hydroxyflavones can be conveniently synthesized from appropriate (E)-1-(3-hydroxy-1-phenyl-1H-pyrazol-4-yl)prop-2-en-1-ones employing Algar–Flynn–Oyamada reaction conditions. Further functionalization of the 5-position of the pyrano[2,3-c]pyrazol-4(2H)-one ring was achieved by employing various Pd-catalyzed coupling reactions of the intermediate 5-triflate. Extensive NMR spectroscopic studies were undertaken using standard and advanced methods to unambiguously determine the structure and configuration of the synthesized compounds. The synthesized 3-hydroxyflavone analogues were characterized by good quantum yields and large Stokes shifts. In addition, the excited-state intramolecular proton transfer (ESIPT) reaction of 5-hydroxypyrano[2,3-c]pyrazol-4(2H)-one from the 5-hydroxy moiety to the carbonyl group in polar protic, polar aprotic, and non-polar solvents was observed, resulting in a well-resolved two-band fluorescence.