The use of small-molecule organocatalysts in organic synthesis has flourished over the past decade ^{[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]}. The advantages of organocatalysts over other catalysts, such as those based on transition-metal complexes, include greater air- stability and commercial availability, lower cost, lack of heavy metals, and lower inherent toxicity. Moreover, organocatalysts can enable access to reactions via different activation modes and often require relatively simple reaction conditions ^{[1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15]}. One novel class of small-molecule organocatalysts is triarylmethyl chlorides (Ar₃CCl), whose catalytic activity is mediated via in situ formation of triarylmethyl carbocations (Ar₃C⁺) ^{[9, 10, 11, 12, 13, 14, 15]}.

Pyrazole-based compounds have received much attention owing to their various biological activities, which include their acting as antitumor ^[16], antifilarial ^[17], antibacterial ^[18], antidepressant ^[19], and gastric-secretion stimulatory agents ^[20], as well as selective inhibitors of cycloxygenase-2 ^[21], and inhibitors of cytokines ^[22].

More specifically, derivatives such as 4'-(arylmethylene)- bis(1H- pyrazol-5-ol)s have been used as dyestuffs ^[23], fungicides ^[24], and pesticides ^[25]. A typical route to one class of these compounds, 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl- 1H- pyrazol-5-ol)s (1), is via the condensation of two equivalents of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) with one equivalent of aromatic aldehydes 3 (Scheme 1) ^{[26, 27, 28, 29, 30, 31, 32, 33, 34]}. Numerous Lewis and Brönsted acid catalysts have been employed to promote this transformation, including cerium(IV) ammonium nitrate ^[26], [Cu(3,4-tmtppa)](MeSO₄)₄ ^[27], 3-  aminopropylat ed silica gel ^[28], 1,3-disulfonic acid imidazolium tetrachloroaluminate ^[29], 1,3,5-tris(hydrogensulfato) benzene ^[30], silica-bonded S-sulfonic acid (SBSSA) ^[31], PEG-OSO₃H ^[32], xanthan sulfuric acid ^[33], and sulfuric acid ([3-(3- silicapropyl)sulfanyl]propyl)ester ^[34]. This reaction has been also performed in PEG-400 at 110 °C ^[35].

Scheme 1. Synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s using trityl chloride.

However, disadvantages of these methods include requirements for (1) difficult-to-prepare catalysts; (2) prolonged reaction times; (3) use of toxic organic solvents; (4) harsh reaction conditions; and (5) tedious work-up procedures. Furthermore, yields are often only moderate. To overcome these limitations, a more efficient, pH-neutral, and easily available catalyst capable of operating under mild conditions would be strongly desirable.

Here we describe our studies examining whether trityl chloride (Ph₃CCl) fulfills the above criteria, as an organocatalyst for the synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl- 1H-pyrazol-5-ol)s from 3-methyl-1-phenyl-1H-pyrazol-5(4H)- one and aromatic aldehydes.

First, we explored the optimal reaction temperature and quantity of Ph₃CCl that was required for the synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s from 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) and benzaldehyde. As shown in Table 1, the best results were obtained with 5 mol% of the catalyst at 60 °C.

Table 1 Optimization of the catalyst amount and temperature on the solvent- free reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) with benzaldehyde. Entry Ph3CCl amount (mol%) Temperature (°C) Time (min) Yield a (%) 1 2.5 60 18 88 2 5 60 12 95 3 7 60 12 95 4 5 50 20 84 5 5 65 12 95 6 2.5 65 15 91 a Yield of isolated product.

Table 1 Optimization of the catalyst amount and temperature on the solvent- free reaction of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) with benzaldehyde.

Next, the solvent demands of the same reaction were examined. A mixture of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2; 2 mmol), benzaldehyde (1 mmol), and Ph₃CCl (0.05 mmol) was reacted at 60 °C in solvent (5 mL) or under solvent-free conditions. As shown in Table 2, the solvent-free method was rapid and very high-yielding, whereas significantly lower yields were obtained from reactions performed in solvent, despite longer reaction times.

Table 2 Effect of solvent on the Ph3CCl-catalyzed condensation of 3-methyl-1- phenyl-1H-pyrazol-5(4H)-one (2) with benzaldehyde. Entry Solvent Temperature (°C) Time (min) Yield a (%) 1 — 60 12 95 2 CH3CN 60 60 53 3 CHCl3 reflux 60 46 4 THF 60 60 50 5 EtOH 60 80 63 6 EtOAc 60 80 71 a Yield of isolated product.

Table 2 Effect of solvent on the Ph3CCl-catalyzed condensation of 3-methyl-1- phenyl-1H-pyrazol-5(4H)-one (2) with benzaldehyde.

To assess the efficiency and scope of the organocatalyst, 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s (1) were synthesized by the condensation of 3-methyl-1- phenyl- 1H-pyrazol-5(4H)-one (2) with different arylaldehydes under the optimized reaction conditions (Table 3). As can be seen, the electronic character of substituents on the aromatic ring of the aldehyde had a negligible effect on the efficiency of the reaction, with all desired products being obtained in high to excellent yields in short reaction time (Table 3, entries 1-15). Moreover, Ph₃CCl successfully catalyzed the reaction when heteroaromatic aldehydes were used, affording 1x, 1y, and 1z. Thus, Ph₃CCl catalysis was efficient and general.

Table 3 Solvent-free synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl- 1H- pyrazol-5-ol)s (1) from 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) and (hetero)arylaldehydes catalyzed by Ph3CCl at 60 °C. Entry R Time (min) Yield a (%) M.p. (°) Found Reported 1 C6H5 12 95 168-170 169-171 [30] 2 4-NO2C6H4 6 93 228-230 225 [30] 3 3-NO2C6H4 5 94 147-149 151-154 [30] 4 2-NO2C6H4 9 95 221-223 221-223 [32] 5 4-CNC6H4 15 92 216-218 212-214 [30] 6 4-Cl-3-NO2C6H4 6 95 235-237 237-238 [30] 7 4-ClC6H4 10 95 213-215 212-214 [32] 8 3-ClC6H4 9 92 151-153 150-152 [35] 9 2-ClC6H4 13 94 234-236 236-237 [32] 10 4-BrC6H4 9 95 181-183 183-185 [30] 11 3-BrC6H4 9 92 172-174 172-175 [32] 12 2-BrC6H5 6 91 248-250 — 13 4-FC6H4 10 97 175-177 182-184 [30] 14 4-MeC6H4 10 96 202-204 203-205 [32] 15 2,5-(MeO)2C6H4 4 94 133-141 — 16 2-Naphthyl 22 94 203-205 204-206 [30] 17 2-Thienyl 17 88 192-194 190-192 [35] 18 2-Furyl 10 74 189-191 189-191 [35] 19 2-Pyridyl 7 86 229-231 230-232 [35] a Yield of isolated product.

Table 3 Solvent-free synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl- 1H- pyrazol-5-ol)s (1) from 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) and (hetero)arylaldehydes catalyzed by Ph3CCl at 60 °C.

In another study, recyclability of the catalyst was investigated. For this purpose, several reactions of 3-methyl-1-phenyl- 1H-pyrazol-5(4H)-one (2) with benzaldehyde in the presence of Ph₃CCl were performed in parallel, and the reaction mixtures were then combined and worked up as per the general method (see Experimental section). The filtrate obtained during the work-up was concentrated to dryness to afford the remaining Ph₃CCl catalyst, which was recycled in another subsequent run of the reaction. The catalytic activity of Ph₃CCl was found to be retained, within the limits of the experimental error, for three successive recycle runs.

In a plausible mechanism (Scheme 2), resonance forms I and II can first be generated from arylaldehyde and Ph₃CCl in a reversible reaction ^{[9, 10, 11, 12, 13, 14, 15]}. To confirm our proposal, benzaldehyde was treated with Ph₃CCl, and then FT-IR, ¹H-NMR, and UV spectra of the resulting mixture were compared with those of benzaldehyde. It was found that: (1) in the FT-IR spectrum, the stretching vibration of aldehyde carbonyl group shifts to a slightly lower frequency because of increased dipole moment character of the carbonyl functionality (IR (nujol): ν_max of C=O in benzaldehyde (1705 cm^-1) decreased to 1697 cm^-1 in the mixture of benzaldehyde and Ph₃CCl ^{[11, 12, 13, 14, 15]}); (2) in the ¹H-NMR spectrum, the aldehyde hydrogen was deshielded, which is in agreement with the increased single-bond character of the carbonyl functional group observed in the FT-IR spectra (¹H-NMR (300 MHz, CDCl₃): δ of the aldehydic hydrogen (9.78) increased to 10.04 in the mixture ^{[11, 12, 13, 14, 15]}); (3) in the ¹³C NMR spectrum, δ of the carbonyl carbon (191.8) increased to 195.2 in the reaction mixture ^[11]; (4) in the UV spectrum (n-hexane), λ_max of absorption of benzaldehyde and Ph₃CCl appeared at 240 and 222 nm, respectively; however, λ_max of the absorption of the complexes of benzaldehyde and trityl carbocation was observed at 245 nm ^{[14, 15]}.

Scheme 2. Proposed mechanism for the condensation of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one with arylaldehydes catalyzed by Ph3CCl.

These results confirmed that resonance forms I and II are present in equilibrium in the reaction medium, as first reported by Kusumoto et al. ^[36]. These resonance forms act as an activated aldehyde, reacting with tautomer IV of 3-methyl-1- phenyl-1H-pyrazol-5(4H)-one (I) providing V, which converts to VI by proton transfer. Intermediate VI can interconvert to VII by loss of Ph₃COH. VII and Ph₃COH then react to give Michael acceptor VIII, Ph₃CCl, and H₂O. VIII subsequently reacts with another molecule of 3-methyl-1-phenyl-1H-pyrazol-5(4H)-one (2) (as tautomer IV) to produce IX. Finally, tautomerization of IX gives the product 1.

This suggested mechanism is supported by data from previous literature ^{[9, 10, 11, 12, 13, 14, 15, 28, 29, 36, 37]} and also by the fact that Ph₃CCl was quantitatively recovered, with no Ph₃COH being detectable (as confirmed by LCMS analysis of the reaction mixture and of an authentic sample of Ph₃COH).

We have developed a novel method for the synthesis of 4,4'-(arylmethylene)-bis(3-methyl-1-phenyl-1H-pyrazol-5-ol)s using commercially available Ph₃CCl as a low-cost and pH- neutral organocatalyst under solvent-free conditions. The advantages of this new method are its efficiency, simplicity, and generality with the high yields and ease of work up and purification being particularly notable.

The authors thank for Research Council of Payame Noor University.