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. 2023 Jun 13;25(24):4462–4467. doi: 10.1021/acs.orglett.3c01437

One-Pot Synthesis of 1-Aryl-3-trifluoromethylpyrazoles Using Nitrile Imines and Mercaptoacetaldehyde As a Surrogate of Acetylene

Kamil Świątek †, Greta Utecht-Jarzyńska †, Marcin Palusiak ‡, Jun-An Ma §,*, Marcin Jasiński †,*
PMCID: PMC10294255  PMID: 37309990

Abstract

graphic file with name ol3c01437_0009.jpg

A synthetically useful approach for one-pot preparation of 1-aryl-3-trifluoromethylpyrazoles using in situ generated nitrile imines and mercaptoacetaldehyde applied as 1 equiv of acetylene is presented. This protocol comprises (3 + 3)-annulation of the mentioned reagents to form 5,6-dihydro-5-hydroxy-4H-1,3,4-thiadiazine, followed by cascade dehydration/ring contraction reactions with p-TsCl. In addition, representative nonfluorinated analogues functionalized with Ph, Ac, and CO2Et groups at the C(3)-position of the pyrazole ring were also prepared by the devised method.

1-Aryl-3-trifluoromethylpyrazole has been identified as a privileged structural motif for a number of bioactive compounds applied as either pharmaceutics or crop protection materials.1 For example, celecoxib is a well-known nonsteroidal anti-inflammatory agent (COX-2 inhibitor),2 whereas SC-560 exhibits anticancer activity (Figure 1).3 More recently introduced to the market, berotralstat acts as an effective plasma kallikrein inhibitor, and it is used in long-term prophylaxis to prevent hereditary angioedema (HAE) attacks.4 Furthermore, many 1-aryl-3-trifluoromethylpyrazoles also exhibit promising antibacterial5 and anticancer6 activity or serve as a key building block for the preparation of more advanced systems of interest in plant biology7 and material sciences.8 For these reasons, there is increasing interest in the development of new synthetic protocols to access 3-trifluoromethylpyrazoles of various substitution patterns, starting with readily available, cheap, and easy to handle building blocks.

Figure 1.

Figure 1

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Structures of selected therapeutics based on a 1-aryl-3-trifluoromethylpyrazole core.

Among the methods available to date, classical condensation of trifluoromethylated 1,3-dicarbonyls or their equivalents with hydrazines is the most often applied strategy to access 3-trifluoromethylpyrazoles.1,9 Also, (3 + 2)-cycloadditions of fluorinated 1,3-dipoles such as 2,2,2-trifluorodiazoethane (CF3CHN2) with appropriate dipolarophiles have been shown to be a powerful approach.10 Importantly, rapid progress in the chemistry of trifluoroacetonitrile imines 1 (Scheme 1), recognized as readily available building blocks for the preparation of 3-CF3-pyrazoles, has been observed in recent years.11,12 Notably, application of this 1,3-dipole, readily accessible in situ via base-mediated dehydrohalogenation of the respective hydrazonoyl halides 2, leads to N-functionalized heterocycles and typically offers excellent control on regio- and chemoselectivity of the cycloaddition step. For example, either electron-rich (vinyl ethers, enamines, and benzynes)11 or electron-deficient dipolarophiles (e.g., cyanoalkenes, nitroolefins, and enones)12 have been demonstrated as suitable reaction partners to access polyfunctionalized products.

Scheme 1. General Strategies for the Synthesis of 1-Aryl-3-trifluoromethylpyrazoles and the Method Reported Herein.

Scheme 1

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The traditional methods toward simple 1-aryl-3-trifluoromethylpyrazoles 3 are limited to (a) cyclocondensations of appropriate trifluoromethylated carbonyl compounds13 with hydrazines and (b) Cu-catalyzed N-arylations of 3-trifluoromethyl-1H-pyrazole (Scheme 1).14 In addition, trifluoromethylation of 3-iodo-1-phenyl-1H-pyrazole under flow conditions is possible as reported by Buchwald (c).15 Nevertheless, the mentioned methods either suffer from regioselectivity issues or require harsh conditions and special equipment. Thus, nitrile imines 1 are revealed as ideal candidates for the preparation of such heterocyclic systems, e.g., through (3 + 2)-cycloaddition with acetylene16 or its surrogates.17

Here we report the one-pot synthesis of 1-aryl-3-trifluoromethylpyrazoles by using 2,5-dihydroxy-1,4-dithiane-2,5-diol as a convenient and safe material for the surrogate of acetylene. The method comprises (3 + 3)-condensation of in situ generated nitrile imine with mercaptoacetaldehyde, followed by p-TsCl-mediated dehydration and spontaneous or thermally induced Eschenmoser sulfide contraction18 of the first formed 4H-1,3,4-thiadiazine derivative (Scheme 2). In addition, a short series of nonfluorinated nitrile imines bearing an aryl (Ph), acyl (Ac), or ester (CO2Et) group at the C termini were checked to give the expected functionalized pyrazoles. Furthermore, some trifluoromethylated products of type 3 were applied for the preparation of three known drugs of selective COX-1 (SC-560) and COX-2 (Celecoxib and Mavacoxib) inhibitory activity.

Scheme 2. Synthesis of 1-Tolyl-3-trifluoromethylpyrazole (3a).

Scheme 2

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For the first experiments, commercially available 2,5-dihydroxy-1,4-dithiane-2,5-diol (4) as a precursor of mercaptoacetaldehyde19 and N-tolyl bromide 2a as a precursor of nitrile imine 1a were selected. Based on our previous experience in reactions of nitrile imines 1 with S-containing reaction partners,20 the reaction of 2a and 4 (1:1) was carried out in dry dichloromethane, at room temperature, using Et3N as a base for in situ generation of nitrile imine, and the expected 5,6-dihydro-4H-1,3,4-thiadiazin-5-ol 5a was formed solely under the applied conditions (Scheme 2).20c In order to get more insight into the planned subsequent dehydration step, the first formed (3 + 3)-annulation product 5a was isolated (95%) and briefly examined in a series of experiments (Table 1). Attempted activation of a hemiaminal group in 5a with excess acetic acid (10 equiv) was in vain, and after standard aqueous workup the unchanged starting material was recovered (entry 1). In contrast, treatment of 5a with aq. HCl (10 equiv, 18% aq) led to a mixture of starting material contaminated with small amounts of its 5-chloro analogue (in a ca. 4:1 ratio, respectively; entry 2). Similar results were noticed for the reaction carried out in a methanolic solution saturated with dry gaseous HCl (entry 3). Thus, substitution at C(5) was favored over the desired elimination pathway under the applied conditions. Also, treatment of 5a with PPh3 (3.0 equiv) showed no changes in the mixture, even after 16 h of refluxing in THF (entry 4). Finally, activation of the OH group in 5a with oxalyl chloride (1.5 equiv), in the presence of excess Et3N (3.0 equiv), led to a complex mixture of unidentified products, but the desired pyrazole 3a was found as a minor component in 26% yield (entry 5). Gratifyingly, replacement of (COCl)2 with p-TsCl suppressed the formation of side products and provided the expected pyrazole 3a (98%), which formed as the exclusive material (entry 6). Noteworthy, in the 1H NMR spectrum of the crude reaction mixture, no signals attributed to 1,3,4-thiadiazine intermediate 6a could be detected, indicating that the anticipated ring contraction in 6a proceeds smoothly at room temperature.

Table 1. Synthesis of Pyrazole 3a: Optimization Study.

entry substrate(s) additives solvent 3a (%)
1 5aa AcOH CH2Cl2 -
2 5aa HCl(aq) CH2Cl2 -b
3 5aa HCl(dry) MeOH -b
4 5aa,c PPh3 THF -
5 5aa (COCl)2 CH2Cl2 26
6 5aa p-TsCl CH2Cl2 98
7 2a + 4d p-TsCl CH2Cl2 67
8 2a + 4d p-TsCle CH2Cl2 94 (91)f
9 2a + 4d p-TsCle DCE 95
10 2a + 4d p-TsCle THF 88
11 2a + 4d p-TsCle toluene 81
12 2a + 4d,g p-TsCle CH2Cl2 95 (93)f
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a

Reaction conditions: a solution of 5a (0.20 mmol) and additive (1.5, 3.0, or 10.0 equiv., see the text) in corresponding solvent (3 mL) were reacted overnight at room temperature; yields are estimated based on 1H NMR spectra of crude mixtures.

b

An ca. 4:1 mixture of starting 5a and its 5-chloro analogue was formed.

c

Reflux.

d

To a solution of 2a (1.0 mmol) and 4 (0.55 mmol) in solvent (12 mL) was added Et3N (10.0 mmol). After 2 h, a solution of p-TsCl (1.5 mmol) in the same solvent (4 mL) was added dropwise, and the resulting mixture was stirred overnight; yields are estimated based on 1H NMR spectra of crude mixtures.

e

2.5 equiv of p-TsCl was used.

f

Isolated yield.

g

7.1 mmol scale (starting with 2.0 g of bromide 2a).

Next, the reaction was carried out in a one-pot manner starting with precursor 2a and a slight excess of dimer 4. After the bromide was fully consumed, excess p-TsCl (1.5 equiv) was added to the reaction mixture, and after 2 h the expected 1-tolyl-3-trifluoromethylpyrazole (3a, 67%) was detected in a crude mixture, along with unconsumed 5a (entry 7). Further increase of the amount of p-TsCl (2.5 equiv) assured almost complete conversion, leading to 3a, which was isolated in excellent 91% yield (entry 8), whereas the change of the reaction medium to nonhalogenated solvents such as THF or toluene slightly decreased conversion (entries 9–11). Finally, the reaction was repeated on a larger scale; starting with 2.0 g of bromide 2a the target pyrazole 3a (93%) was obtained in comparable yield (entry 12).

With the optimized conditions in hand, a series of trifluoromethylated hydrazonoyl bromides 2a–2p were involved in the study. In all the cases the formation of the expected 4,5-unsubstituted pyrazoles was observed in high yields. Thus, alkyl (Me, i-Pr), alkoxy (OMe, OBn), and fluoroalkyl (CF3) substituents; halogens (F, Cl, Br); as well as functional groups such as cyano, nitro, sulfonamide, and ester could efficiently be introduced on the phenyl ring (Scheme 3). Notably, in the case of 2o bearing the NO2 group, the respective 1,3,4-thiadiazine 6o was found in a crude reaction mixture under the applied conditions. A small sample of this intermediate was isolated by preparative TLC and fully characterized by spectroscopic methods (Figure 2); however, its gradual desulfurization both during the NMR measurements (in CDCl3) and upon standing at room temperature was observed. Thus, the reactions of mercaptoacetaldehyde with strongly electron-deficient nitrile imines 1i and 1k–1p were carried out in DCE solutions, and the resulting mixtures were additionally heated under reflux to accelerate the final ring-contracting step.

Scheme 3. One-Pot Synthesis of 3-Trifluoromethylated 1-Arylpyrazoles 3a–3p: Scope of Nitrile Imines.

Scheme 3

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DCE was used instead of DCM, and the resulting mixture was additionally refluxed for 2 h.

Figure 2.

Figure 2

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(a) Diagnostic chemical shifts in 1H NMR (600 MHz, CDCl3) of the vinylene unit in 6o and 3o and (b) X-ray structure of 6x.

To briefly check the generality of the devised protocol, a series of selected nonfluorinated nitrile imines bearing Ph, CO2Et, or Ac groups at the C-termini of the 1,3-dipole were also examined in reaction with mercaptoacetaldehyde to provide the expected 1-arylpyrazoles 3q–3y (Scheme 4). Introduction of both an electron-withdrawing acetyl group and the electron-deficient Ar substituent in chloride 2 (X = Cl, CO2Et, NO2) provided remarkably stable intermediate 1,3,4-thiadiazines 6, which in comparison to CF3 analogues required harsher conditions (e.g., heating the crude mixture at 100 °C, either in DMSO or neat) to accomplish the final desulfurization. The structure of representative derivative 6x, adopting well-defined boat-like conformation at the 4H-1,3,4-thiadiazine ring in the solid state (for details, see Supporting Information), was unambiguously confirmed by X-ray analysis (Figure 2). The possible mechanism of the studied ring contraction also deserves a comment. Based on the observed trends in stability of 6 and taking into account the noncatalyzed nature of the desulfuration step (proceeds upon standing), we assume that 1,3,4-thiadiazine 6 could undergo spontaneous 6π-electrocyclization, leading to bicyclic thiirane intermediate A (Scheme 5). Subsequent extrusion of the sulfur atom afforded aromatized pyrazole 3 as the final product.

Scheme 4. Synthesis of Nonfluorinated 1-Arylpyrazoles 3q–3y.

Scheme 4

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Crude mixture was heated at 100 °C, in DMSO.

Scheme 5. Proposed Mechanism.

Scheme 5

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Finally, to utilize the devised method for the preparation of more complex pyrazole derivatives, compound 3c was applied in the synthesis of SC-560. Selective deprotonation at C(5) of 3c with n-BuLi, followed by trapping of the first formed anion with elemental iodine, afforded the respective iodide 7c (91%). Subsequent Pd-catalyzed cross-coupling of the latter with 4-chlorophenylboronic acid provided SC-560 (8) in a high overall yield of 78% (Scheme 6). Similarly, sulfonamide-functionalized 3-trifluoromethylpyrazole 3m was converted into the corresponding 5-iodo derivative 7m; next, by using appropriate arylboronic acids, two further biologically active pyrazoles, namely, celecoxib (9) and mavacoxib (10), were obtained through Suzuki–Myiaura cross-coupling in 51% and 56% yield (for two steps), respectively.

Scheme 6. Synthesis of Celecoxib, Mavacoxib, and SC-560: (a) n-BuLi, TMEDA, and THF at −78 °C and Then I2 at rt for 30 min and (b) Arylboronic Acid, Pd(PPh3)4, K2CO3, and THF/H2O, at 80 °C, for 2 Days.

Scheme 6

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In summary, a straightforward one-pot protocol for the preparation of 3-trifluoromethyl-1-arylpyrazoles using in situ generated nitrile imines and mercaptoacetaldehyde was developed. The presented method features readily available, safe, and easy to handle starting materials, mild reaction conditions, scalability, and wide tolerance of functional groups. It can also be applied for the synthesis of nonfluorinated analogues including derivatives bearing, at C(3) of the pyrazole ring, useful functional groups such as Ac and CO2Et. Hence, the current protocol can be recommended for the preparation of fluorinated and nonfluorinated 4,5-unsubstituted 1-arylpyrazoles, which not only are important structural scaffolds for numerous materials of practical significance but also can be considered as useful building blocks for postcyclizative functionalizations toward more complex pyrazole derivatives.

Acknowledgments

This research was supported by the University of Lodz (K.Ś.: No. 8/DGB/2022) and National Natural Science Foundation of China (J.-A.M.: No. 92156025). The authors also thank Ms. Sylwia Kudra, Ms. Magdalena Mróz, and Ms. Agata Matusiak for their technical assistance.

Data Availability Statement

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

Supporting Information Available

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.3c01437.

  • Experimental procedures, characterization data, and NMR spectra of all compounds (PDF)

  • FAIR data, including the primary NMR FID files, for compounds 2m, 2v–2y, 3a–3y, 6o, 6x, 7c, 7m, and 8–11 (ZIP)

The authors declare no competing financial interest.

Supplementary Material

ol3c01437_si_001.pdf (4.3MB, pdf)
ol3c01437_si_002.zip (157.8MB, zip)

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Associated Data

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Supplementary Materials

ol3c01437_si_001.pdf (4.3MB, pdf)
ol3c01437_si_002.zip (157.8MB, zip)

Data Availability Statement

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

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