Preparation of novel acyl pyrazoles and triazoles by means of oxidative functionalization reactions

2.1 Preparation of novel acyl pyrazoles

To start our preparative chemistry, we decided to prepare a number of N-acyl pyrazoles with various functionality on the aldehyde precursor. In each case, a mixture of 1 eq. of the aldehyde, 5, and 1.1 eq. of pyrazole was treated with 0.75 eq. of oxoammonium salt 4 and the reaction mixture was heated at 54°C for 3 h (Figure 2). Following this, the products were isolated by extraction, with no need for chromatographic purification. We focused initially on benzaldehydes bearing electron donating groups. In most cases, the N-acyl pyrazole was isolated in modest yield (6a–6c). An exception was when 4-(dimethylamino)benzaldehyde was used, in which case no reaction was observed (6d). We broadened the scope by next using 2-napthaldehyde as the aldehyde component. The desired N-acyl pyrazole, 6e, was obtained in 58% yield. Heterocyclic aldehydes could be used as reagents, a case in point being 1-methylindole-3-carboxaldehyde where the N-acyl pyrazole, 6f, could be prepared in 34% yield. However, when using 2-pyridinecarbaldehyde, no reaction was observed (6g). To complete our screen, we moved beyond benzaldehydes as substrates and instead chose (4-isobutylphenyl)acetaldehyde as a starting material, the corresponding N-acyl pyrazole, 6h, being obtained in 64% yield.

Figure 2

Oxidative amidation of aldehydes with pyrazole to prepare acyl pyrazoles. Reaction was carried out in a sealed vial using 5 (1 mmol, 1 eq.). Isolated yield after purification.

2.2 Preparation of novel acyl triazoles

To expand the study, we next varied the azole coupling partner, we turned our attention to the preparation of triazoles. The N-acyl triazole products could have interesting biological properties based on previous literature [27,28,29]. Unlike the oxidative amidation with pyrazole, when preparing 1,2,3-triazoles or 1,2,4-triazoles, there is the potential for the formation of regioisomers; the acyl group being situated on either the 1-, 2-, or 4-position on the triazole ring. We initially employed the same synthetic approach as we had used for the preparation of acyl pyrazoles. While we did observe good product conversion, not all the aldehyde starting material was consumed, even after prolonged reaction times. This poses a challenge when it comes to product isolation. Separation of the acyl triazole from unreacted aldehyde is not a trivial process. To circumvent this, we decided to employ a different methodology. We have shown previously that acyl pyrazoles can be prepared using nitroxide 3 as a catalyst and sodium persulfate as a terminal oxidant [20]. The reaction is performed at 50°C for 24 h, using pyridine as a base. The reason for this is that the initial step of the reaction involves a thermally-induced homolytic cleavage of sodium persulfate to generate two equivalents of the sulfate radical anion ( SO 4 − ), which in turn oxidizes nitroxide 3 to the corresponding oxoammonium cation. This then performs the oxidative amidation reaction via the intermediacy of an acyl pyridinium ion and, in so doing, generating hydroxylamine 2. The nitroxide is regenerated by means of another sulfate radical anion, thereby closing the catalytic cycle (Figure 3). Using this preparative approach, we have prepared a series of seven acyl triazoles (Figure 4; 7a–7g). In most cases only one of the regioisomers of the product was formed, but in one (7b) we observed a mixture of the two, the N-1 functionalized compound predominating. When the benzaldehyde starting material bore a nitro or cyano group, while the N-acyl azole was observed in initial assay of the crude product mixture (7c and 7d), it could not be isolated by aqueous/organic extraction. We attribute this to the fact that the carbonyl carbon in the newly formed amide is extremely electron-poor making it highly susceptible to nucleophilic acyl substitution to generate the corresponding carboxylic acid.

Figure 3

Catalytic cycle for oxidative amidation.

Figure 4

Oxidative amidation of aldehydes with triazole to prepare acyl triazoles. Reaction performed in a sealed vial using 5 (1 mmol, 1 eq.). Isolated yield after purification, unless noted otherwise. ^aProduct conversion determined by GC-MS.

4.1 General considerations

NMR spectra (¹H, ¹³C, and ¹⁹F) were recorded at 300 K on a Brüker Avance Ultra Shield 300 MHz, Bruker DRX-400 400 MHz, or Brüker Avance 500 MHz spectrometer. ¹H-NMR spectra were referenced to residual chloroform (7.26 ppm) in CDCl₃. ¹³C-NMR spectra were referenced to CDCl₃ (77.16 ppm). ¹⁹F-NMR spectra were referenced to hexafluorobenzene (−161.64 ppm) [30]. Reactions were monitored by an Agilent Technologies 7820A Gas Chromatograph attached to a 5975 Mass Spectrometer, ¹⁹F-NMR, and/or by TLC on silica gel plates (60 Å porosity, 250 μm thickness). TLC analysis was performed using a solution of 8:2 hexanes:ethyl acetate and visualized with UV light.

Deuterated chloroform (CDCl₃) was purchased from Cambridge Isotope Laboratories. 4-acetamido-TEMPO (ACT, 3) and 4-Acetamido-2,2,6,6-tetramethylpiperidin-1-oxoammonium nitrate (4) were prepared using previously reported protocols [31,32]. All aldehydes and heterocycles used were purchased from Oakwood Chemicals, Sigma-Aldrich, or Alfa Aesar and distilled before use if required.

4.2 Procedure for the preparation of acyl pyrazoles from aldehydes

To a 14 mL capacity vial equipped with a stir bar was added the aldehyde (5, 1 mmol, 1 eq.), 4-acetamido-2,2,6,6-tetramethylpiperidin-1-oxoammonium nitrate (4, 206 mg, 0.75 eq.), and pyrazole (75 mg, 1.1 eq.). The vial was closed tightly and the contents heated in an oil bath at 50°C. Upon completion of the heating step, the vial and its contents were allowed to cool to room temperature and then the product mixture was transferred to a 250 mL separatory funnel using acetonitrile (1 mL) and the vial was washed with hexanes (50 mL) and this was also added to the separatory funnel. Deionized water (50 mL) was added to the separatory funnel and the aqueous layer then was washed twice with hexanes (2 × 25 mL). The organic washes were combined 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 afford the product 6.

4.3 Procedure for the preparation of acyl triazoles from aldehydes

To a 14 mL capacity vial equipped with a stir bar were added the aldehyde (5, 1 mmol, 1 eq.), pyridine (404 µL, 5 eq.), acetonitrile (2 mL), 3 (63 mg, 0.30 eq.), triazole (83 mg, 1.2 eq.), and sodium persulfate (1.190 g, 5 eq.). The vial was closed tightly, and the contents heated in an oil bath at 50°C for 24 h. Upon completion of the heating step, the vial and its contents were allowed to cool to room temperature and then the product mixture was transferred to a 250 mL separatory funnel, and the vial was washed with deionized water (20 mL) and this was also added to the separatory funnel. The contents of the separatory funnel were then further diluted with deionized water (30 mL) and the aqueous layer then washed three times with hexanes (1 × 50 mL followed by 2 × 25 mL). The organic washes were combined and washed with 0.5 M hydrochloric acid (15 mL), saturated aqueous sodium bicarbonate (20 mL), and deionized water (15 mL). The organic layer was dried over sodium sulfate, and the solvent removed in-vacuo to afford the product 7.