Ambient-Temperature Synthesis of (E)-N-(3-(tert-Butyl)-1-methyl-1H-pyrazol-5-yl)-1-(pyridin-2-yl)methanimine

We report the ambient-temperature synthesis of novel (E)-N-(3-(tert-butyl)-1-methyl-1H-pyrazol-5-yl)-1-(pyridin-2-yl)methanamine 3 in 81% yield by a condensation reaction between 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 and 2-pyridinecarboxaldehyde 2 in methanol using magnesium sulfate as a drying agent. The N-pyrazolyl imine 3 was full characterized by IR, 1D, and 2D NMR spectroscopy, mass spectrometry, and elemental analysis.


Introduction
Pyrazole is a five-membered heterocyclic system containing three carbon atoms and two nitrogen atoms in adjacent positions [1]. Pyrazole and its derivatives have attracted a great deal of attention in organic and medicinal chemistry due to their wide range of pharmacological and biological activities [2][3][4][5][6][7]. For example, apixaban is employed to prevent blood clots [7], sildenafil is a cyclic GMP-specific phosphodiesterase inhibitor to treat erectile dysfunction [8], benzydamine hydrochloride is a non-steroidal anti-inflammatory drug [9], and axitinib is a selective tyrosine kinase inhibitor to treat advanced renal cell carcinoma [10], among others marketed drugs possessing this pyrazole structural motif, as shown in Figure 1.

Introduction
Pyrazole is a five-membered heterocyclic system containing three carbon atoms and two nitrogen atoms in adjacent positions [1]. Pyrazole and its derivatives have attracted a great deal of attention in organic and medicinal chemistry due to their wide range of pharmacological and biological activities [2][3][4][5][6][7]. For example, apixaban is employed to prevent blood clots [7], sildenafil is a cyclic GMP-specific phosphodiesterase inhibitor to treat erectile dysfunction [8], benzydamine hydrochloride is a non-steroidal anti-inflammatory drug [9], and axitinib is a selective tyrosine kinase inhibitor to treat advanced renal cell carcinoma [10], among others marketed drugs possessing this pyrazole structural motif, as shown in Figure 1. In particular, 5-aminopyrazole has been extensively employed as an important azaheterocyclic template for the preparation of a variety of bicyclic N-heterocycles with interesting applications in medicinal chemistry [11] and material science [12,13]. In this context, we have recently employed N- (5-pyrazolyl)imines in the aza-Diels-Alder cycloaddition reaction using electrophilic α-oxoketene and aryne intermediates for the expeditious syntheses of pyrazolopyrid-4-ones [14] and isoquinolines [15], respectively. Due to the   In particular, 5-aminopyrazole has been extensively employed as an important azaheterocyclic template for the preparation of a variety of bicyclic N-heterocycles with interesting applications in medicinal chemistry [11] and material science [12,13]. In this context, we have recently employed N-(5-pyrazolyl)imines in the aza-Diels-Alder cycloaddition reaction using electrophilic α-oxoketene and aryne intermediates for the expeditious syntheses of pyrazolopyrid-4-ones [14] and isoquinolines [15], respectively. Due to the considerable interest of 5-aminopyrazole as an important aza-heterocyclic template for the preparation of N-(5-pyrazolyl)imines, and its application in the formation of pyrazole-containing heterocycles [14][15][16], we herein report the synthesis and full characterization of novel N-pyrazolyl imine 3 through the uncatalyzed condensation reaction of 5-aminopyrazole 1 with hetaryl aldehyde 2 under mild reaction conditions.

Results and Discussion
We describe the synthesis of N-pyrazolyl imine 3 by a condensation reaction between equimolar amounts of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 and pyridinecarboxaldehyde 2 in methanol (HPLC grade, ≥99.9%) under stirring at ambient temperature for 24 h, using an excess of magnesium sulfate as a drying agent (Scheme 1). After the specified reaction time, the mixture was filtered, and the solvent was removed by a rotary evaporator under vacuum. The resulting crude product was purified by flash chromatography on silica gel using a mixture of DCM/MeOH (40:1, v/v) as an eluent to afford N-pyrazolyl imine 3 in an 81% yield. As expected, the water released in the condensation process was trapped by the drying agent to displace the equilibrium towards the imine product. It should be noted that a complete spectroscopic and analytical characterization was performed in this work (Materials and Methods). Initially, the structure of N-pyrazolyl imine 3 was determined by IR, 1D NMR spectroscopy, mass spectrometry, and elemental analysis (Figures S1-S6, Figure 2A). Then, the examination of 2D NMR spectra, including HSQC ( Figure  considerable interest of 5-aminopyrazole as an important aza-heterocyclic template for the preparation of N-(5-pyrazolyl)imines, and its application in the formation of pyrazolecontaining heterocycles [14][15][16], we herein report the synthesis and full characterization of novel N-pyrazolyl imine 3 through the uncatalyzed condensation reaction of 5-aminopyrazole 1 with hetaryl aldehyde 2 under mild reaction conditions.

Results and Discussion
We describe the synthesis of N-pyrazolyl imine 3 by a condensation reaction between equimolar amounts of 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 and pyridinecarboxaldehyde 2 in methanol (HPLC grade, ≥99.9%) under stirring at ambient temperature for 24 h, using an excess of magnesium sulfate as a drying agent (Scheme 1). After the specified reaction time, the mixture was filtered, and the solvent was removed by a rotary evaporator under vacuum. The resulting crude product was purified by flash chromatography on silica gel using a mixture of DCM/MeOH (40:1, v/v) as an eluent to afford Npyrazolyl imine 3 in an 81% yield. As expected, the water released in the condensation process was trapped by the drying agent to displace the equilibrium towards the imine product. It should be noted that a complete spectroscopic and analytical characterization was performed in this work (Materials and Methods). Initially, the structure of N-pyrazolyl imine 3 was determined by IR, 1D NMR spectroscopy, mass spectrometry, and elemental analysis (Figures S1-S6, Figure 2A). Then, the examination of 2D NMR spectra, including HSQC ( Figure  In the IR spectrum, the absorption bands at 1588 and 1568 cm −1 were assigned to C = N stretching vibrations. It should be noted that C=N stretching modes are mostly depicted as combinational bands with C=C stretching vibrations. In addition, C-N stretching vibrations were observed at 1245 and 1290 cm −1 . In the MS spectrum, the molecular ion peak was observed at 242 m/z with a 58% intensity, while the base peak was detected at 227 m/z with a 100% intensity, corresponding to the elimination of a methyl group. The 1 H NMR spectrum of 3 recorded in CDCl3 showed the existence of two methyl groups at 1.32 and 3.94 ppm, as well as one methine of the pyrazole ring at 6.17 ppm (Table 1). In the downfield region, four methines of the pyridine ring appeared in a range between 7 and 8 ppm. The signal of the azomethine group was observed as a singlet at 8.66 ppm, indicating that the condensation process was successful. The 13 C{ 1 H} NMR and DEPT spectra of 3 showed 12 carbon signals, consisting of one azomethine, four quaternary carbons, five aromatic methines, and two methyls (Table 1 and Figure 2A). The HSQC spectrum recorded in CDCl3 enabled the assignment of all protons to the directly bonded carbons. Thus, the signals of C(CH3)3, NCH3, and CH=N groups were assigned at 30.6, 34.8, and 159.1 ppm, respectively. Moreover, the C-4 signal was observed at 88.7 ppm, which is in good agreement with the high electron density of the carbon atom at position 4 of π-excedent pyrazole systems [14][15][16]. In Table 1 and Figure 2B, the correlation C-H observed in the HMBC experiment for quaternary carbons C-3, C-5, and C-2′ is summarized, highlighting the correlation at 2 J for CH=N to C-2′ (154.7 ppm). Other important correlations were the tert-butyl group with C-3 (161.4 ppm) at 3 J, while NCH3 and CH=N signals cor-    In the IR spectrum, the absorption bands at 1588 and 1568 cm −1 were assigned to C = N stretching vibrations. It should be noted that C=N stretching modes are mostly depicted as combinational bands with C=C stretching vibrations. In addition, C-N stretching vibrations were observed at 1245 and 1290 cm −1 . In the MS spectrum, the molecular ion peak was observed at 242 m/z with a 58% intensity, while the base peak was detected at 227 m/z with a 100% intensity, corresponding to the elimination of a methyl group. The 1 H NMR spectrum of 3 recorded in CDCl 3 showed the existence of two methyl groups at 1.32 and 3.94 ppm, as well as one methine of the pyrazole ring at 6.17 ppm (Table 1). In the downfield region, four methines of the pyridine ring appeared in a range between 7 and 8 ppm. The signal of the azomethine group was observed as a singlet at 8.66 ppm, indicating that the condensation process was successful. The 13 C{ 1 H} NMR and DEPT spectra of 3 showed 12 carbon signals, consisting of one azomethine, four quaternary carbons, five aromatic methines, and two methyls (Table 1 and Figure 2A). The HSQC spectrum recorded in CDCl 3 enabled the assignment of all protons to the directly bonded carbons. Thus, the signals of C(CH 3 ) 3 , NCH 3 , and CH=N groups were assigned at 30.6, 34.8, and 159.1 ppm, respectively. Moreover, the C-4 signal was observed at 88.7 ppm, which is in good agreement with the high electron density of the carbon atom at position 4 of π-excedent pyrazole systems [14][15][16]. In Table 1 and Figure 2B, the correlation C-H observed in the HMBC experiment for quaternary carbons C-3, C-5, and C-2 is summarized, highlighting the correlation at 2 J for CH=N to C-2 (154.7 ppm). Other important correlations were the tert-butyl group with C-3 (161.4 ppm) at 3 J, while NCH 3 and CH=N signals correlated with C-5 (148.9 ppm) at 3 J. The quaternary carbon of the tert-butyl group was observed in the upfield region at 32.4 ppm. Ultimately, the COSY experiment helped to identify the four aromatic methines of the pyridine ring C-3 , C-4 , C-5 , and C-6 at 121.5, 136.7, 125.3, and 149.9 ppm, respectively.  In summary, we report the ambient-temperature synthesis of N-pyrazolyl imine 3 in good yield through an uncatalyzed condensation reaction between 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 and 2-pyridinecarboxaldehyde 2 in the presence of magnesium sulfate as a drying agent. This protocol is distinguished by its ease of operation, high atom economy, simple isolation of the imine, and clean reaction profile. It should be noted that N-pyrazolyl imine 3 could be employed as an aza-heterocyclic template for obtaining fused pyrazole derivatives with potential applications in medicinal chemistry and materials science.

General Information
The 3-(tert-butyl)-1-methyl-1H-pyrazol-5-amine 1 was synthesized using a known method [14]. 2-pyridinecarboxaldehyde 2 was acquired from Sigma-Aldrich (CAS 1121-60-4) and used without previous purification. The starting materials were weighed and handled in air at ambient temperature. Silica gel aluminum plates (Merck 60 F 254 , Darmstadt, Germany) were used for analytical TLC. A Shimadzu FTIR 8400 spectrophotometer (Scientific Instruments Inc., Seattle, WA, USA) equipped with an attenuated reflectance accessory was used for acquiring the IR absorption spectrum. A Bruker Avance 400 spectrophotometer (Bruker BioSpin GmbH, Rheinstetten, Germany) was used to record 1 H and 13 C{ 1 H} NMR spectra at 25 • C using frequencies of 400 and 101 MHz, respectively. The chemical shifts of 1 H and 13 C{ 1 H} NMR spectra were referenced with tetramethylsilane (δ = 0.0 ppm). Alternatively, the chemical shifts of 1 H and 13 Figure S1: MS spectrum of the compound 3; Figure S2: IR spectrum of the compound 3; Figure S3: 1H NMR spectrum of the compound 3; Figure S4: Expansion 1H NMR spectrum of the compound 3; Figure S5: 13C{1H} NMR and DEPT-135 spectra of the compound 3; Figure S6: Expansion 13C{1H} NMR and DEPT-135 spectra of the compound 3; Figure S7: HSQC 2D C-H correlation spectrum of the compound 3; Figure S8: HMBC 2D C-H correlation spectrum of the compound 3; Figure S9: Expansion HMBC 2D C-H correlation spectrum of the compound 3; Figure S10: COSY 2D H-H correlation spectrum of the compound 3.
Author Contributions: Investigation, data curation, writing-original draft preparation, D.B.; resources, writing-review and editing, J.C.; conceptualization, data curation, writing-original draft preparation, J.-C.C. All authors have read and agreed to the published version of the manuscript.

Funding:
The APC was sponsored by MDPI.

Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.

Data Availability Statement:
The data presented in this study are available in this article.