(3,5-Di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone

Abstract

The acyl pyrazole derivative (3,5-di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone was prepared simply and rapidly in 86% isolated yield by means of an oxidative functionalization reaction of an aldehyde with pyrazole. A substoichiometric quantity of 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium nitrate was used as the oxidant. The reaction was performed solvent-free and in the absence of a base, making it a clean, green approach. The mixture of aldehyde, pyrazole, and the oxidant was heated at 55 °C for 3 h, and then, the product was isolated in analytically pure form via extraction with no need for column chromatography.

1. Introduction

Within the field of heterocyclic chemistry, N-acyl azoles are attracting significant attention. As well as being of interest themselves [1,2,3,4], they are considered activated amides and can participate in transamidation reactions and other functional-group interconversions [5]. One approach to the preparation of N-acyl azoles is by means of an oxidative amidation reaction [6,7]. Aldehydes serve as the carbonyl-containing progenitor of the amide and are oxidatively functionalized with an amine [8,9,10]. Our research group has focused some significant effort on the preparation of N-acyl pyrazoles using such an approach and we have developed a series of methodologies centered around the use of oxoammonium salts and their corresponding nitroxide analogs as reagents and catalysts (Figure 1) [5,11,12,13,14]. The most widely used oxoammonium salt is 4-acetamido-2,2,6,6-tetramethylpiperidine-1-oxoammonium tetrafluoroborate (AcNH-TEMPO⁺BF₄⁻, 1) [15,16,17]. However, when using 1 as a reagent to prepare N-acyl pyrazoles via the oxidative amidation of aldehydes with pyrazole, a super-stoichiometric quantity of the salt is required [5]. This is because the spent oxidant, hydroxylammonium salt (3), undergoes a comproportionation reaction with 1 to generate nitroxide (2) [18]. As a result, a sacrificial equivalent of 1 is required to achieve complete oxidation of the substrate. More recently, we have explored the use of other oxoammonium salts for the oxidative amidation reaction (Figure 2). We found that nitrate salt (4) not only is effective, but can also be used in substoichiometric amounts [14]. In addition, the reaction can be performed in the absence of an added base. This makes the approach easier, cleaner, and more efficient than that using 1. Here, we use a modified version of this methodology for the preparation of (3,5-di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone (6) from 3,5-di-tert-butylbenzaldehyde (5).

2. Results and Discussion

To prepare N-acyl pyrazole (6), we treated a mixture of 1 eq of 3,5-di-tert-butylbenzaldehyde (5) and 1.1 eq of pyrazole with 0.75 eq of oxoammonium salt (4) (Figure 3). The reaction mixture was heated at 54 °C for 3 h. Following this, the product was isolated by means of an aqueous/organic extraction. An 86% yield of (3,5-di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone (6) was obtained. As well as being able to perform the reaction in the absence of an added base, it is also solvent-free. This adds to the green credentials of the protocol [19].

The novel N-acyl pyrazole product (6) was characterized via IR and NMR spectroscopy as well as high-resolution mass spectrometry. The IR spectrum of 6 shows a characteristic CO stretch at 1701 cm⁻¹ for the amide functionality. The ¹³C-NMR spectrum is comprised of ten signals, which is in agreement with the number of unique carbon environments in 6. ¹H-NMR shows signals for the aromatic ring, the pyrazole ring, and the two tert-butyl groups. The high-resolution mass spectrum confirms the identity of the product.

3. Materials and Methods

3.1. General Experimental Procedure

Chemicals were purchased from Oakwood Chemicals (Estill, SC, USA), Sigma-Aldrich (St. Louis, MO, USA), or Acros Organics (Geel, Belgium) and distilled before use if required. NMR spectra (¹H at 400 MHz and ¹³C at 101 MHz) were obtained in deuterated chloroform at 300 K using a Brüker DRX-400 spectrometer (Brüker, Billerica, MA, USA). ¹H-NMR spectra were referenced to residual CHCl₃ (7.26 ppm) in CDCl₃. ¹³C-NMR spectra were referenced to CDCl₃ (77.16 ppm). Deuterated chloroform (CDCl₃) [CAS 865-49-6] was purchased from Cambridge Isotope Laboratories (Tewksbury, MA, USA). Reactions were monitored using an Agilent Technologies 7820A gas chromatograph attached to a 5975 mass spectrometer (Santa Clara, CA, USA) and/or via TLC on silica gel plates (60 Å porosity, 250 μm thickness). TLC analysis was performed using UV light. Infrared spectra were recorded using a Bruker Alpha FTIR spectrometer using an attenuated total reflection (ATR) diamond crystal (Brüker, Billerica, MA, USA). High-resolution mass spectra were collected using an Applied Biosystems QSTAR Elite instrument equipped with an electrospray ionization (ESI) source, calibrated using Agilent LC/MS tuning mix (Waltham, MA, USA).

3.2. Preparation of (3,5-Di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone (6)

To a 15 mL reaction vial equipped with a stir bar, we added 3,5-di-tert-butylbenzaldehyde (5) (1 mmol, 218 mg, 1 eq), 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxoammonium nitrate (0.75 mmol, 206 mg, 0.75 eq), and pyrazole (1.1 mmol, 75 mg, 1.1 eq). The vial was closed tightly and the contents heated for 3 h in an oil bath set at 54 °C. Upon completion of the heating step, the reaction mixture was quenched with acetonitrile (1 mL) and the vial contents were transferred to a glass separatory funnel, rinsing the reaction vial with hexanes (50 mL). Deionized water (50 mL) was added to the separatory funnel and the organic layer washed and separated. The aqueous layer was then washed with two aliquots of hexanes (2 × 25 mL). The organic washes were then combined, placed into a separatory funnel, and washed with 2 M hydrochloric acid (15 mL) and saturated aqueous sodium bicarbonate (20 mL). The organic layer was dried over sodium sulfate, and the solvent removed in vacuo to produce the product, (3,5-di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone (6), as a white solid (245 mg, 86% yield).

¹H-NMR (400 MHz, CDCl₃) δ 8.42 (d, J = 2.6 Hz, 1H), 7.97–7.90 (m, J = 1.9 Hz, 2H), 7.79 (d, J = 0.8 Hz, 1H), 7.68 (t, J = 1.8 Hz, 1H), 6.54–6.49 (m, 1H), 1.36 (s, 18H). ¹³C-NMR (101 MHz, CDCl₃) δ 167.6, 150.7, 144.4, 131.0, 130.6, 127.5, 126.0, 109.3, 35.1, 31.5. IR (neat, ν/cm⁻¹): 1701 (C=O). HRMS (ESI) m/z: calculated for C₁₈H₂₅N₂O [M + H]⁺, 285.1967; found, 285.1965. Copies of ¹H- and ¹³C-NMR, and IR spectra of 6 are available in the Supplementary Materials.

4. Conclusions

An acyl pyrazole derivative was prepared simply and rapidly in 86% isolated yield by means of an oxoammonium salt-mediated oxidative functionalization reaction of an aldehyde with pyrazole. The product could be isolated in analytically pure form via extraction with no need for column chromatography.

Author Contributions

Conceptualization, N.E.L.; methodology, G.P.W., K.E.D. and A.L.S.; validation, G.P.W., K.E.D. and A.L.S.; formal analysis, G.P.W., K.E.D. and A.L.S.; resources, N.E.L.; data curation, G.P.W., K.E.D. and A.L.S.; writing—original draft preparation, N.E.L.; writing—review and editing, G.P.W., K.E.D., A.L.S. and N.E.L.; supervision, A.L.S. and N.E.L.; project administration, N.E.L.; funding acquisition, N.E.L. All authors have read and agreed to the published version of the manuscript.

Data Availability Statement

Data are contained within the article or Supplementary Materials.

Acknowledgments

We thank Adam Graichen for the equipment support for high-resolution mass spectrometry and Vitaliy Gorbatyuk for the equipment support for NMR spectroscopy.

Conflicts of Interest

The authors declare no conflict of interest.

Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Figures

Figure 1. (a) Oxidative amidation of aldehydes with pyrazole to prepare acyl pyrazoles. (b) Oxoammonium salt 1, and its nitroxide and hydroxylammonium analogs 2, and 3.

Figure 2. Oxidative amidation of aldehydes with pyrazole to prepare acyl pyrazoles using a substoichiometric quantity of oxoammonium salt 4.

Figure 3. Preparation of (3,5-di-tert-butylphenyl)(1H-pyrazol-1-yl)methanone (6) from 3,5-di-tert-butylbenzaldehyde (5) using a substoichiometric quantity of oxoammonium salt 4.

Supplementary Materials

The following supporting information can be downloaded online: Copies of ¹H- and ¹³C-NMR, and IR spectra of 6.

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