Efficient One-Pot, Two-Component Modular Synthesis of 3,5-Disubstituted Pyrazoles

Abstract

The pyrazole scaffold is one of the most prevalent and important tool in medicinal chemistry. Here, we report a method for preparing 3,5-diarylpyrazoles in good to excellent yield by reacting hydrazones of aryl aldehydes with substituted acetophenones in ethanol in the presence of dimethyl sulfoxide/cat. I₂/cat. HCl. The reverse process, reacting hydrazones of substituted acetophenones with aryl aldehydes under the same conditions, also provides 3,5-diarylpyrazoles in good to excellent yields. Reaction of hydrazones of aldehydes with 2′-aryloxy ketones in the presence of cat. HCl in ethanol and the catalyst-free reaction of phenacyl bromides with hydrazones of aldehydes in ethanol also gave good to excellent yields of 3,5-diarylpyrazoles.

Introduction

The pyrazole scaffold is one of the most prevalent and important scaffolds in medicinal chemistry. Many pyrazoles have been shown to exhibit a wide range of biological activities such as antimicrobial, anticonvulsant, anti-inflammatory, antifungal, antiviral, and anticancer activity, to name just a few.¹ Several pyrazole-containing compounds are commercial drugs such as sildenafil and celecoxib.¹ Pyrazoles have been also used as ligands for transition-metal-catalyzed cross-coupling reactions.²

Among the many pyrazoles that exhibit biological activity are 3,5-diarylpyrazoles.¹ Various procedures have been developed to prepare these compounds.^1,3 However, many of these procedures use expensive or hazardous transition-metal catalysts⁴ or undesirable solvents,⁴ or stoichiometric or excess amounts of harsh or hazardous reagents (LiHMDS, tBuOLi, tBuOK, n-BuLi),⁵ or require the preparation of substituted chalcones,⁶ or specialized reagents,⁷ or the preparation or formation of potentially dangerous diazo or azido substrates or intermediates.⁸ Here, we report that 3,5-diarylpyrazoles can be prepared in good yield by reacting substituted acetophenones or aryl aldehydes with the hydrazones of aromatic aldehydes or acetophenones in the presence of catalytic amounts of I₂ and/or acid and a modest excess of dimethyl sulfoxide (DMSO) in ethanol.

Results and Discussion

We initiated our studies by determining whether 3,5-diarylpyrazoles could be formed by reacting substituted 2′-bromoacetophenones with aryl hydrazones using 2′-bromoacetophenone (1) benzalhydrazone (2) as model substrates. We anticipated that if the reaction between 1 and 2 occurred preferentially at the carbonyl of 1, then the resulting intermediate I would undergo further reaction (vide infra) to produce the desired 3,5-diarylpyrazole 3 (Scheme 1).

Scheme 1. Formation of Pyrazole 3 via Intermediate I.

A mixture of 1 equiv of 1 and 1.2 equiv of 2 in EtOH was stirred at room temperature for 5 min and then refluxed. The starting bromoacetophenone is completely consumed after 15–25 min as judged by thin-layer chromatography (TLC). After 30 min reflux, the mixture was subjected to workup and chromatography, which provided pyrazole 3 in a 30% yield (Table 1, entry 1). Longer reaction times did not give better yields. The structure of 3 was confirmed by X-ray crystallography (see the Supporting Information). Increasing the number of equiv of 2 to 1.4 or 2.2 gave only modest increases in yield (Table 1, entries 2 and 3). However, when 1.4 equiv of 2 was added to a solution of 1 in the refluxing ethanol and the reflux continued for 0.5 h, the yield of 3 increased to 92% (Table 1, entry 4). Reducing the equiv of 2 to 1.2 equiv resulted in a decrease in the yield (Table 1, entry 5). Applying these conditions using 4′-methoxy-2-bromoacetophenone (4) produced pyrazole 5 in 86% yield (Table 1, entry 6). 2-Phenoxyacetophenone (5) failed to undergo reaction with hydrazone 2 to give pyrazole 3 under these conditions (Table 1, entry 7).

Table 1. Optimization of Pyrazole Formation Using Phenacyl Derivatives and Benzal Hydrazone.

entry	phenacyl derivative	equiv 2	time (h)	yieldc (%)
1	1	1.2	0.5a	30
2	1	2.2	0.5a	39
3	1	1.4	0.5a	39
4	1	1.4	0.5b	92
5	1	1.2	0.5b	80
6	4	1.4	0.5b	86
7	5	1.4	48	NRd

^aCompound 2 was added to a solution of phenacyl derivative at room temperature and then the reaction mixture was refluxed.

^bCompound 2 was added to a refluxing solution of phenacyl derivative.

^cIsolated yield.

^dNo reaction.

Benzal hydrazone can potentially attack phenacyl bromides at the carbonyl carbon to give intermediate I (pathway a, Scheme 2) or at the α-position to give intermediate IV (pathway b, Scheme 2). Busch et al. reported that the reaction of bromoacetophenone with excess hydrazine hydrate in ethanol at −5 °C occurs at the α-position to give 2-hydrazinyl-1-phenylethan-1-one in 60% yield.⁹ However, pathway b does not occur under our conditions as this route would produce 3,4-disubstituted pyrazoles that were not isolated from the reactions. We propose two possible pathways, c and d, for 3,5-diarylpyrazole formation. In pathway c, intermediate I tautomerizes/aromatizes to intermediate II, which then cyclizes to give intermediate III. Elimination of HBr from intermediate III gives the 3,5-disubstituted pyrazoles. In pathway d, intermediate I loses Br^– to form resonance stabilized cation V, which can cyclize to give intermediate VI. Deprotonation of VI gives intermediate VII, which upon tautomerization/aromatization yields the 3,5-disubstituted pyrazoles.

Scheme 2. Proposed Mechanisms for the Formation of 3,5-Disubstituted Pyrazoles from Phenacyl Bromides and Benzal Hydrazone.

To make the procedure more broadly applicable, we decided to use ketones instead of phenacyl bromides and generate the haloketone in situ using iodine. Refluxing a mixture of 2.0 equiv 2, 1.0 equiv of acetophenone, and 1.0 equiv of iodine in ethanol at a reflux for 1.5 h afforded 3 in 80% yield (Table 2, entry 1). Decreasing the number of equivalents of benzalhydrazone to 1.5 or 1.2 resulted in a decrease in yield (Table 2, entries 2 and 3). Decreasing the amount of iodine to 0.1 equiv resulted in only a trace amount of 3 (Table 2, entry 4).

Table 2. Optimization of the Reaction of Acetophenone (7) with Hydrazone 2 for the Production of Pyrazole 3.

entry	equiv 2	I2 (equiv)	DMSOb	HClc	H2SO4e	time (h)	yielda (%)
1	2.0	1.0				1.5	80
2	1.5	1.0				1.5	76
3	1.2	1.0				1.5	45
4	2.0	0.1				24	trace
5	1.5	0.1	DMSO			24	trace
6	1.5	0.1	DMSO	used		5	85
7	1.2	0.1	DMSO	used		5	85
8	1.2	0.05	DMSO	used		8	85
9	1.2	0.1	DMSOd	used		4	85
10	1.2		DMSO	used		48	81
11	1.2		DMSO		used	5	0
12	1.2		DMSO	used	used	5	83
13	1.2		DMSO			24	0

^aIsolated yield.

^bThree equivalents of DMSO added unless stated otherwise.

^c75 μL of HCl was used per 1.5 mmol of ketone.

^dFour equivalents of DMSO added.

^eCatalytic amounts of H₂SO₄ is used (25 μL per 1.5 mmol of ketone).

While this work was in progress, Aegurla and Peddinti reported the synthesis of 3,5-diarylpyrazoles using a process very similar to that described above wherein aryl hydrazones, generated in situ, were reacted with substituted acetophenones in the presence of 1 equiv of I₂ in EtOH at 70 °C for 12 h.¹⁰ They also showed that the reaction of α-iodoacetophenone with aryl hydrazones in refluxing EtOH at 70 °C provided 3,5-diarylpyrazoles. They proposed that both reactions proceeded via an intermediate similar to I (Schemes 1 and 2, I in place of Br) and pathway d, though, in our opinion, pathway c is also possible.

Inspired by the successful synthesis of 3 from phenacyl halides and aryl hydrazones (possibly via route c, Scheme 2), we investigated whether pyrazole 3 could be prepared via the route outlined in Scheme 3. We reasoned that the reaction of acetophenone (7) with hydrazone 2 may result in the reversible formation of pyrazoline intermediate X via intermediates VIII and IX, which, in the presence of an oxidant, would be irreversibly oxidized to pyrazole 3.

Scheme 3. Proposed Alternative Route to Pyrazole 3.

As DMSO/I₂ is a well-known green catalyst for iodine-mediated oxidations,^11,12 including the oxidation of pyrazolines to pyrazoles,¹³ we first explored the route outlined in Scheme 3 using these reagents. However, performing the reaction using 0.1 equiv I₂ and 3.0 equiv DMSO resulted in only trace amounts of the desired product after 24 h reflux and much of the starting materials remained unconsumed (Table 2, entry 5). Therefore, this reaction was repeated except a cat. amount of HCl was added, which we anticipated would promote the formation of imine VIII and cyclization of intermediate IX. Under these conditions, pyrazole 3 was obtained in an 85% yield after 5 h reflux (Table 2, entry 6). Decreasing the amount of iodine to 0.05 equiv or increasing the amount of DMSO to 4.0 equiv resulted respectively in increasing or decreasing of the reaction time (Table 2, entries 7–9). As DMSO/HCl is also a known oxidant,¹⁴ we attempted the reaction in the absence of I₂ but with a cat. amount of HCl. Under these conditions, pyrazole 3 was formed in an 81% yield, but the reaction took 48 h (Table 2, entry 10). Increasing the amount of cat. HCl by 2- or 3-fold did not result in an increase in yield or reaction time. The combination of DMSO and cat. H₂SO₄ (Table 2, entry 11) did not result in the formation any pyrazole after 5 h; however, when performing the reaction in the presence of both cat. HCl and cat. H₂SO₄, the reaction was complete within 5 h and pyrazole 3 was obtained in 83% yield (Table 2, entry 12). No pyrazole product was formed when the reaction was performed with just DMSO (no I₂ or acid, Table 2, entry 13).

We prepared a series of pyrazoles (3, 16–25) by reacting acetophenones (7–12) with aryl hydrazones (2, 13–15) in refluxing EtOH and in the presence of either cat. HCl/4 equiv DMSO/cat. I₂ (method A), cat. HCl/4 equiv DMSO (method B), or, to a lesser extent, cat. HCl/cat. H₂SO₄/4 equiv DMSO (method C) (Table 3). Method A provided the pyrazoles in good to excellent yield usually within 10–16 h. The exception was the 4-amino derivative 19, which did not give any pyrazole product. Acetophenones bearing electron-donating groups tended to take longer to react than acetophenone (i.e., entries 1–3 versus entries 4–6). Method B also gave the pyrazoles in good yield, though, as expected, the reaction times were longer than with method A. Method C was examined for the preparation of pyrazoles 3, 16, 18, and 19 (entries 4, 7, and 10). This method was successful in all four cases, though the yields were slightly lower compared to method A and the purification more challenging.

Table 3. Synthesis of 3,5-Disubstituted Pyrazoles from Aryl Ketones and Aldehyde Hydrazones.

^aMethod A: Ketone added to 1.2 equiv of the aldehyde hydrazone in ethanol followed by cat. aq HCl. Reflux for 1 h and then add 4 equiv DMSO and 10 mol % I₂.

^bMethod B: Same as method A, except no I₂ added.

^cMethod C: Same as method B, except cat. HCl and cat. H₂SO₄ added at the beginning.

^dIsolated yield.

We also attempted to prepare 3,5-diaryl-4-aryloxypyrazoles by reacting 2-phenoxyacetophenone (5) with aryl hydrazones using methods A or B; however, this did not afford 4-aryloxypyrazoles, but rather the 4-unsubstituted pyrazoles (Table 5). We later found that the reaction does not require DMSO or I₂ to proceed and requires just cat. HCl (entry 5), suggesting that the reaction proceeds in a manner similar to when using bromoacetophenone. The HCl probably helps promote the formation of intermediate I (Schemes 1 or 2, where Br is replaced with OPh) and may also aid in the loss of PhOH by acting as general acid. The fact that the reaction of hydrazone 2 with 2-phenoxyacetophenone in the absence of added acid did not produce pyrazole 3 (Table 1, entry 7) indicates that the presence of acid is essential for pyrazole formation when using 2-phenoxyacetophenone as one of the substrates. In the case of the reaction of hydrazone 2 with 2-bromoacetophenone (1) (i.e., Table 1, entry 4), no exogenous acid was required for pyrazole formation. This may be due to the formation of HBr during the reaction, which helps promote the formation of intermediate I.

Table 5. Synthesis of 3,5-Diarylpyrazoles Using 2-Phenoxyacetophenone.

^aMethod A: Ketone added to 1.2 equiv of the aldehyde hydrazone in ethanol followed by cat. aq HCl. Reflux for 1 h and add 4 equiv DMSO and 10 mol % I₂.

^bMethod B: Same as method A, except no I₂ added.

^cIsolated yield.

^dCat. HCl, EtOH, reflux 16 h.

The reverse approach, using ketone hydrazones (26 and 27) and benzaldehydes (28–32), also provided pyrazoles in good yield (Table 4). Pyrazoles can be prepared in very good yield using either approach or either methodology A or B, as evidenced by the synthesis of pyrazoles 20, 22, and 23 (Table 3, entries 13 and 14 and 17–20 and Table 4, entries 1 and 6–9).

Table 4. Synthesis of 3,5-Diarylpyrazoles Using Ketone Hydrazones and Aryl Aldehydes.

^aMethod A: Ketone added to 1.2 equiv of the aldehyde hydrazone in ethanol followed by cat. aq HCl. Reflux for 1 h and then add 4 equiv DMSO and 10 mol % I₂.

^bMethod B: Same as method A, except no I₂ added.

^cIsolated yield.

Conclusions

In summary, we have developed a method for preparing 3,5-diarylpyrazoles in good to excellent yields by reacting aryl or ketone hydrazones with acetophenones or aryl aldehydes in EtOH and using only catalytic amounts of I₂ or acid and a modest excess of DMSO to promote the reaction. The substrates are readily available or easily prepared and the reagents common and very inexpensive. 3,5-Diarylpyrazoles were also obtained in good yield by reacting 2-bromoacetophenones or 2-phenoxyacetophone/cat. HCl with aryl hydrazones. We are now employing these procedures to prepare libraries of 3,5-diarylpyrazoles, which will be examined as potential anticancer agents.

Experimental Section

General Information

All reagents, ketones, aldehydes, and solvents were purchased from commercial suppliers and used without purification unless stated otherwise. Hydrazones 2,¹⁵13,¹⁶14,¹⁷15,¹⁸ and 27(19) were prepared using literature procedures.

Chemical shifts (δ) for ¹H NMR spectra run in DMSO-d₆ are reported in parts per million (ppm) relative to DMSO residual solvent protons (δ 2.5). Chemical shifts for ¹³C NMR spectra run in DMSO-d₆ are reported in ppm relative to the solvent residual carbon (δ 39.5). Chemical shifts (δ) for ¹H NMR spectra run in acetone-d₆ are reported in ppm relative to DMSO residual solvent protons (δ 2.05). Chemical shifts for ¹³C NMR spectra run in DMSO-d₆ are reported in ppm relative to the solvent residual carbon (δ 30.8). Peaks in NMR spectra are described as follows: singlet (s), broad singlet (bs), doublet (d), triplet (t), apparent doublet (appd), apparent triplet (appt), and doublet of doublets (dd). Samples for high-resolution positive-ion electrospray ionization mass spectrometry (HRMS-ESI⁺) were prepared in 1:1 CH₃CN/H₂O + 0.2% formic acid.

Synthesis of [1-(3,4-Dimethoxy-phenyl)-ethylidene]-hydrazine (26)

3,4-Dimethoxyacetophenone (0.02 mol, 3.6 g, 1.0 equiv) was added to a stirred solution of 80% hydrazine hydrate (0.12 mol, 7 mL, 6.0 equiv) in ethanol (20 mL). A catalytic amount of acetic acid (ca. 0.25 mL) was added, and the mixture was stirred at room temperature for 5 min and then refluxed for 3 h. After stirring at room temperature overnight, the mixture was concentrated by rotary evaporation, diluted with water, and the pH adjusted to 4–5 using 6 N HCl. The formed precipitate was filtered, washed with water, and dried. ¹H NMR (CDCl₃, 300 MHz): δ 7.63 (d, J = 1.7 Hz, 1H), 7.33 (dd, J = 1.8, 8.3 Hz, 1H), 6.86 (d, J = 8.3 Hz, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 2.28 (s, 3H); ¹³C NMR (CDCl₃, 72 MHz): 157.1, 150.5, 148.8, 131.4, 119.8, 110.2, 109.0, 55.9, 14.8.

General Procedure for the Synthesis of Pyrazoles from Phenacyl Bromides and Benzal Hydrazone

A solution of phenacyl bromide (1.5 mmol, 1.0 equiv) in ethanol (10 mL) was heated to reflux and then benzal hydrazone (2.1 mmol, 252 mg, 1.4 equiv) was added. The mixture was refluxed for 30 min, cooled, diluted with water, and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were washed with water (1 × 20 mL), dried over anhydrous magnesium sulfate, concentrated by rotary evaporation, and purified by column chromatography or crystallization.

3,5-Diphenylpyrazole (3)

Pale yellow solid. Crystals for X-ray diffraction studies were obtained by crystallization in 20% EtOAc–hexane, 304 mg, 92%, mp 201–203 °C (lit.:¹⁹ 202–204 °C). ¹H NMR (DMSO-d₆, 500 MHz): δ 13.41 (s, 1H), 7.89 (bs, 2H), 7.84 (bs, 2H), 7.45 (bs, 4H), 7.33 (bs, 2H), 7.19 (s, 1H). ¹³C NMR (DMSO-d₆, 120 MHz): δ 151.4, 143.3, 133.5, 128.8, 128.0, 127.4, 125.0; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₃N₂ (M + 1H)⁺, 221.1073; found 221.1072.

3-(4-Methoxyphenyl)-5-phenyl-1H-pyrazole (6)

Purified by column chromatography using 30% EtOAc–hexane. Amorphous yellow solid, 323 mg, 86%, ¹H NMR (DMSO-d₆, 500 MHz): δ 13.27 (s, 1H), 7.85 (bs, 12H), 7.79 (bs, 2H), 7.44 (bs, 2H), 7.33 (bs, 1H), 7.07–7.03 (m, 3H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 158.9, 151.2, 143.2, 133.7, 128.6, 127.3, 126.4, 125.0, 121.2, 114.2, 98.7, 55.0; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₅N₂O (M + 1H)⁺, 251.1179; found 251.1175.

General Procedure for the Synthesis of 3,5-Diarylpyrazoles from Reaction of Ketones and Aldehyde Hydrazones

Method A

To 1.5 mmol of the ketone (ketone hydrazone in case of reverse method A) in ethanol (10 mL) was added 1.8 mmol of the aldehyde hydrazone (aldehyde in case of reverse method A), followed by 75 μL HCl. The reaction mixture was refluxed for 1 h and then 6.0 mmol DMSO and 0.15 mmol iodine were added. The reaction mixture was refluxed for specified time and monitored by TLC. The reaction mixture was then cooled to room temperature, quenched with 5% aq sodium thiosulfate (30 mL), and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were washed with water (1 × 20 mL), dried over anhydrous magnesium sulfate, and concentrated by rotary evaporation. The crude product was purified by column chromatography or crystallization.

Method B

To 1.5 mmol of the ketone (ketone hydrazone in case of reverse method B) in ethanol (10 mL) was added 1.8 mmol of the aldehyde hydrazone (aldehyde in case of reverse method B) followed by 75 μL HCl. The reaction mixture was refluxed for 1 h and then 6.0 mmol DMSO was added. The reaction mixture was refluxed for specified time and monitored by TLC. The reaction mixture was then cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were washed with water (1 × 20 mL), dried over anhydrous magnesium sulfate, concentrated by rotary evaporation, and purified by column chromatography or crystallization.

Method C

To 1.5 mmol of the ketone in ethanol (10 mL) added 1.8 mmol of the aldehyde hydrazone, followed by 75 μL HCl and 25 μL H₂SO₄. The reaction mixture was refluxed for 1 h and then 6.0 mmol DMSO was added. The reaction mixture was refluxed for specified time and monitored by TLC. The reaction mixture was then cooled to room temperature, quenched with water (30 mL), and extracted with EtOAc (3 × 20 mL). The combined EtOAc extracts were washed with water (1 × 20 mL), dried over anhydrous magnesium sulfate, concentrated by rotary evaporation, and purified by column chromatography or crystallization.

3,5-Diphenylpyrazole (3)

Two hundred eighty milligrams, 85% (method A), 267 mg, 81% (method B), 274 mg, and 83% (method C). Identical spectral data to that obtained using phenacyl bromide and benzal hydrazone as described above.

3-(4-Hydroxyphenyl)-5-phenyl-1H-pyrazole (16)

Purified by column chromatography using a gradient of 30–50% EtOAc–hexane. Amorphous yellow solid, 258 mg, 73% (method A), 244 mg, 69% (method B), 233 mg, 66% (method C). ¹H NMR (acetone-d₆, 500 MHz): δ 8.8 (bs, 1H), 7.89 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.5 Hz, 2H), 7.43 (appt, J = 7.4 Hz, 2H), 7.32 (appt, J = 7.4 Hz, 2H), 6.99 (s, 1H), 6.94 (d, J = 8.5 Hz, 2H); ¹³C NMR (acetone-d₆, 120 MHz): δ 159.3, 134.3, 130.5, 129.5, 128.6, 127.1, 124.9, 117.5, 100.5; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₃N₂O (M + 1H)⁺, 237.1022; found 237.1021.

4-(5-(3-Methoxyphenyl)-1H-pyrazol-3-yl)phenol (17)

Purified by column chromatography using a gradient of 50% EtOAc–hexane. Amorphous yellow solid, 283 mg, 71% (method A). ¹H NMR (acetone-d₆, 500 MHz): δ 8.8 (bs, 1H), 7.71 (d, J = 8.3 Hz, 2H), 7.45 (s, 1H), 7.44 (d, J = 8.2 Hz, 1H), 7.31 (appt, J = 8.0 Hz, 1H), 6.99 (s, 1H), 6.91 (d, J = 8.6 Hz, 2H), 6.88 (d, J = 8.3 Hz, 1H), 3.88 (s, 3H); ¹³C NMR (acetone-d₆, 120 MHz): δ 160.0, 159.4, 131.6, 128.6, 119.6, 117.5, 115.2, 112.4, 100.7, 56.5; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₅N₂O₂ (M + 1H)⁺, 267.1128; found 267.1127.

3-(3-(4-Hydroxyphenyl)-1H-pyrazol-5-yl)phenol (18)

Purified by column chromatography using a gradient of 50–80% EtOAc–hexane. Amorphous yellow solid, 268 mg, 71% (method A), 242 mg, 64% (method C). ¹H NMR (acetone-d₆, 500 MHz): δ 8.61 (bs, 1H), 7.71 (d, J = 8.5 Hz, 2H), 7.34–7.38 (m, 2H), 7.25 (appt, J = 8.0 Hz), 6.92–6.93 (m, 3H), 6.83 (dd, J = 7.9, 2.5 Hz, 1H); ¹³C NMR (acetone-d₆, 120 MHz): δ 159.5, 159.3, 135.5, 131.6, 128.6, 125.0, 118.6, 117.4, 116.6, 114.1, 100.5; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₃N₂O₂ (M + 1H)⁺, 253.0971; found 253.0970.

4-(5-Phenyl-1H-pyrazol-3-yl)aniline (19)

Purified by column chromatography using a gradient of 60–80% EtOAc–hexane. Two hundred eleven milligrams, 60% (method B), 215 mg, 61% (method C). ¹H NMR (DMSO-d₆, 500 MHz): δ 12.97 (bs, 1H), 7.83 (d, J = 6.3 Hz, 2H), 4.49 (d, J = 6.6 Hz, 2H), 7.43 (appt, J = 7.1 Hz, 2H), 7.31 (appt, J = 7.1 Hz, 1H), 6.91 (s, 1H), 6.64 (d, J = 8.5 Hz, 2H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 148.7, 128.6, 127.2, 126.0, 124.9, 113.8, 97.4; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₄N₃ (M + 1H)⁺, 236.1182; found 236.1182.

3-(3,4-Dimethoxyphenyl)-5-phenyl-1H-pyrazole (20)

Purified by column chromatography using 40% EtOAc–hexane. Amorphous yellow solid, 323 mg, 77% (method A), 315 mg, 75% (method B), 336 mg, 80% (reverse B). ¹H NMR (DMSO-d₆, 500 MHz): δ 13.2 (bs, 1H), 7.86 (d, J = 7.4 Hz, 2H), 7.45–7.47 (m, 3H), 7.39 (d, J = 8.2 Hz, 1H), 7.34 (appt, J = 7.4 Hz, 1H), 7.14 (s, 1H), 7.02 (d, J = 8.2 Hz, 1H); 3.86 (s, 3H), 3.80 (s, 3H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 148.9, 148.6, 128.7, 127.6, 125.0, 117.5, 111.9, 108.9, 99.0, 55.5; HRMS-ESI⁺ (m/z) calcd for C₁₇H₁₇N₂O₂ (M + 1H)⁺, 281.1285; found 281.1284.

3-(3,4-Dimethoxyphenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (21)

Purified by column chromatography using 30% EtOAc–hexane. Amorphous orange solid, 449 mg, 86% (method A), 444 mg, 85% (method B). ¹H NMR (DMSO-d₆, 500 MHz): δ 13.43 (s, 1H), 8.07 (d, J = 5.8 Hz, 2H), 7.79 (bs, 2H), 7.45 (s, 1H), 7.38 (d, J = 7.7 Hz, 1H), 7.27 (s, 1H), 7.04 (d, J = 7.4 Hz, 1H); 3.86 (s, 3H), 3.79 (s, 3H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 149.0, 144.0, 137.7, 125.5, 117.6, 112.0, 109.0, 99.6, 55.5; ¹⁹F NMR (DMSO-d₆, 470 MHz): δ 61.19; HRMS-ESI⁺ (m/z) calcd for C₁₈H₁₆F₃N₂O₂ (M + 1H)⁺, 349.1158; found 349.1155.

5-(4-Bromophenyl)-3-phenyl-1H-pyrazole (22)

Crystallized from 80% aqueous ethanol. Pale yellow solid, 404 mg, 90% (method A), 386 mg, 86% (method B), 413 mg, 92% (reverse A and B). Mp 212–213 °C. ¹H NMR (DMSO-d₆, 500 MHz): δ 13.42 (bs, 1H), 7.84 (d, J = 7.9 Hz, 2H), 7.82 (d, J = 8.5 Hz, 2H), 7.65 (d, J = 8.5 Hz, 2H), 7.47 (appt, J = 7.7 Hz, 2H), 7.34 (appt, J = 7.4 Hz, 1H), 7.23 (s, 1H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 132.2, 129.4, 128.4, 127.6, 125.6, 121.2, 100.4; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₂BrN₂ (M + 1H)⁺, 301.0158; found 301.0158.

3-(3-(4-Bromophenyl)-1H-pyrazol-5-yl)phenol (23)

Crystallized from 80% aqueous ethanol. Four hundred twenty-five milligrams, 90% (method A), 402 mg, 85% (method B), 435 mg, 92% (reverse A), 425 mg, 90% (reverse B). Mp 220–221 °C. ¹H NMR (acetone-d₆, 500 MHz): δ 12.61 (s, 1H), 8.57 (s, 1H), 7.84 (d, J = 8.0 Hz, 2H), 7.60 (d, J = 8.3 Hz, 2H), 7.34 (s, 1H), 7.33 (s, 1H), 7.28 (appt, J = 7.3 Hz, 1H), 7.09 (s, 1H), 6.85 (d, J = 7.3 Hz, 1H); ¹³C NMR (acetone-d₆, 120 MHz): δ 157.9, 131.7, 130.0, 127.2, 121.0, 116.7, 115.1, 112.3, 99.8; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₂BrN₂O (M + 1H)⁺, 315.0128; found 315.0126.

5-Phenyl-3-(thiophen-2-yl)-1H-pyrazole (24)

Purified by column chromatography using a gradient of 10–20% EtOAc–hexane. Amorphous yellow solid, 264 mg, 78% (method A), 272 mg, 80% (method B). ¹H NMR (acetone-d₆, 500 MHz): δ 12.56 (s, 1H), 7.85 (d, J = 7.4 Hz, 2H), 7.44–7.47 (m, 3H), 7.41 (d, J = 4.9 Hz, 1H), 7.36 (appt, J = 7.1 Hz, 1H), 7.10 (dd, J = 4.9, 3.6 Hz, 1H), 6.99 (s, 1H); ¹³C NMR (acetone-d₆, 120 MHz): δ 128.9, 128.1, 127.5, 125.3, 124.6, 123.8, 99.5; HRMS-ESI⁺ (m/z) calcd for C₁₃H₁₁N₂S (M + 1H)⁺, 227.0638; found 227.0637.

5-(3-Methoxyphenyl)-3-(thiophen-2-yl)-1H-pyrazole (25)

Purified by column chromatography using 30% EtOAc–hexane. Amorphous yellow solid, 285 mg, 74% (method A), 304 mg, 79% (method B). ¹H NMR (acetone-d₆, 500 MHz): δ 12.61 (s, 1H), 7.48 (d, J = 3.7 Hz, 1H), 7.42–7.45 (m, 3H), 7.38 (appt, J = 7.9 Hz, 1H), 7.12 (dd, J = 4.9, 3.6 Hz, 1H), 7.02 (s, 1H), 6.95 (dd, J = 6.8, 1.6 Hz, 1H), 3.88 (s, 3H); ¹³C NMR (acetone-d₆, 120 MHz): δ 162.1, 131.8, 129.3, 126.5, 125.6, 119.5, 115.7, 112.4, 101.6, 56.6; HRMS-ESI⁺ (m/z) calcd for C₁₄H₁₂N₂OS (M + 1H)⁺, 257.0743; found 257.0743.

3-(3,4-Dimethoxyphenyl)-5-(3-methoxyphenyl)-1H-pyrazole (33)

Purified by column chromatography using 50% EtOAc–hexane. Amorphous yellow solid, 377 mg, 81% (reverse A), 386 mg, 83% (reverse B). ¹H NMR (acetone-d₆, 500 MHz): δ 12.64 (bs, 1H), 7.50 (s, 1H), 7.48 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.39 (appt, 1H, J = 7.8 Hz, 1H), 7.08 (s, 1H), 6.97 (d, J = 8.1 Hz), 6.89 (dd, J = 8.1, 2.2, 1H), 3.83 (s, 3H), 3.81 (s, 6H); ¹³C NMR (acetone-d₆, 120 MHz): δ 162.0, 151.5, 151.3, 135.4, 131.6, 126.4, 119.8, 119.6, 115.2, 113.8, 112.4, 111.0, 101.0, 57.0, 56.5; HRMS-ESI⁺ (m/z) calcd for C₁₈H₁₉N₂O₃ (M + 1H)⁺, 311.1390; found 311.1390.

3-(3-(3,4-Dimethoxyphenyl)-1H-pyrazol-5-yl)phenol (34)

Purified by column chromatography using 60% EtOAc–hexane. Amorphous yellow solid, 360 mg, 81% (reverse A), 373 mg, 84% (reverse B). ¹H NMR (acetone-d₆, 500 MHz): δ 9.85 (bs, 1H), 7.48 (d, J = 1.7 Hz, 1H), 7.37–7.40 (m, 2H), 7.34 (d, J = 7.6 Hz, 1H), 7.25 (appt, J = 7.8 Hz, 1H), 7.00 (d, J = 7.2 Hz, 1H), 6.99 (s, 1H), 6.82 (dd, J = 7.6, 1.7 Hz), 3.86 (s, 3H), 3.82 (s, 3H); ¹³C NMR (acetone-d₆, 120 MHz): δ 158.1, 149.4, 149.1, 130.2, 118.0, 116.6, 115.2, 112.4, 109.4, 99.6, 56.0; HRMS-ESI⁺ (m/z) calcd for C₁₇H₁₇N₂O₃ (M + 1H)⁺, 297.1234; found 297.1233.

3-(4-Bromophenyl)-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (35)

Crystallized from 80% aqueous ethanol. Five hundred seven milligrams, 92% (reverse A), 496 mg, 90% (reverse B). Mp 227–229 °C. ¹H NMR (DMSO-d₆, 500 MHz): δ 8.06 (d, J = 7.9 Hz, 1H), 7.81 (d, J = 8.5 Hz, 4H), 7.67 (d, J = 8.4 Hz, 2H), 7.37 (s, 1H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 131.7, 127.8 (q, J = 31.2 Hz), 127.0, 125.7, 125.5, 125.3, 123.1, 121.0, 100.8; ¹⁹F NMR (DMSO-d₆, 470 MHz): δ 61.28; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₁BrF₃N₂ (M + 1H)⁺, 367.0052; found 367.0051.

3-(4-Bromophenyl)-5-(3-methoxyphenyl)-1H-pyrazole (36)

Crystallized from 80% aqueous ethanol. Four hundred and forty-four milligrams, 90% (reverse A and B). Mp 169–171 °C. ¹H NMR (DMSO-d₆, 500 MHz): δ 7.82 (d, J = 8.3 Hz, 2H), 7.65 (d, J = 8.3 Hz, 2H), 7.41–7.43 (m, 2H), 7.38 (appt, J = 8.1 Hz, 1H), 7.26 (s, 1H), 6.93 (d, J = 8.1 Hz, 1H), 3.82 (s, 3H); ¹³C NMR (DMSO-d₆, 120 MHz): δ 159.6, 131.6, 129.9, 127.0, 120.6, 117.4, 113.5, 110.4, 100.0, 55.1; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₄BrN₂O (M + 1H)⁺, 329.0284; found 329.0284.

5-(3-Methoxyphenyl)-3-phenyl-1H-pyrazole (37)

Purified by column chromatography using 30% EtOAc–hexane. Amorphous yellow solid, 308 mg, 82% (method A), 338 mg, 90% (method B). ¹H NMR (acetone-d₆, 500 MHz, 120 °C): δ 12.75 (1H, s), 7.89 (s, 2H), 7.46 (s, 4H), 7.36 (s, 2H), 7.13 (s, 1H), 6.92 (s, 1H), 3.86 (s, 3H); ¹³C NMR (DMSO-d₆, 120 MHz, 120 °C): δ 159.3, 129.0, 127.9, 126.9, 124.7, 117.2, 113.0, 110.5, 99.2, 54.8; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₅N₂O (M + 1H)⁺, 251.1179; found 251.1178.

3-(3-Phenyl-1H-pyrazol-5-yl)phenol (38)

Purified by column chromatography using 40% EtOAc–hexane. Amorphous yellow solid, 248 mg, 70% (method A), 262 mg, 74% (Table 5, entry 5). ¹H NMR (acetone-d₆, 500 MHz): δ 12.48 (s, 1H), 8.46 (s, 1H), 7.88 (d, J = 7.4 Hz, 2H), 7.44 (appt, J = 7.4 Hz, 2H), 7.32–7.36 (m, 3H), 7.27 (appt, J = 7.7 Hz, 1H), 7.05 (s, 1H), 8.83 (dd, J = 8.3, 1.3 Hz, 1H); ¹³C NMR (acetone-d₆, 120 MHz): δ 159.7, 131.7, 130.6, 129.6, 127.2, 118.6, 116.7, 114.1, 101.4; HRMS-ESI⁺ (m/z) calcd for C₁₅H₁₃N₂O (M + 1H)⁺, 237.1022; found 237.1022.

3-Phenyl-5-(4-(trifluoromethyl)phenyl)-1H-pyrazole (39)

Purified by column chromatography using 15% EtOAc–hexane. Amorphous yellow solid, 268 mg, 62% (method A), 290 mg, 67% (method B). ¹H NMR (acetone-d₆, 500 MHz): δ 12.77 (1H, s), 8.12 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 7.4 Hz, 2H), 7.78 (d, J = 8.0 Hz), 7.48 (appt, J = 7.4 Hz, 2H), 7.38 (appt, J = 7.4 Hz, 1H), 7.26 (s, 1H); ¹³C NMR (acetone-d₆, 120 MHz): δ 128.9, 128.2, 125.7, 125.6, 125.3, 100.3; ¹⁹F NMR (acetone-d₆, 470 MHz): δ 63.24; HRMS-ESI⁺ (m/z) calcd for C₁₆H₁₂F₃N₂ (M + 1H)⁺, 289.0947; found 289.0946.

Supporting Information Available

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acsomega.8b02304.

• Crystallographic data (CIF)

• Copies of NMR spectra for all pyrazoles, copies of NMR spectra of pyrazole 26, and X-ray crystal structure of 3,5-diphenylpyrazole 3 (PDF)

The authors declare no competing financial interest.