Pyrazoles in the Intersection of Mesomeric Betaines and N-Heterocyclic Carbenes: Formation of NHC Selenium Adducts of Pyrazolium-4-aminides

Abstract

Starting from 4-nitropyrazole, eight mesoionic pyrazolium-4-aminides were prepared by a six-step reaction sequence. The deprotonation of 1,2-disubstituted 4-amido-1H-pyrazolium salts by an anion exchange resin in its hydroxide form is the final step of the synthesis. A tautomeric equilibrium between the mesoionic compounds (pyrazolium-4-aminides) and N-heterocyclic carbenes (pyrazol-3-ylidenes) can be formulated; however, the NHC tautomers were not detected by means of NMR spectroscopy in polar aprotic solvents such as DMSO-d ₆ or MeCN-d ₃. Apart from tautomerism, anionic N-heterocyclic carbenes can be formulated as a result of a deprotonation of the mesoionic compounds­. Trapping reactions were performed with selenium, which resulted in the formation of pyrazole-3-selenones. Methylation at the selenium atom gave the corresponding 3-(methylselanyl)-4-amido-1H-pyrazolium salts, which were deprotonated to give new mesomeric betaines, 3-(methylselanyl)-1H-pyrazolium-4-aminides as unique compounds­. DFT-calculations as well as ⁷⁷Se NMR spectroscopic measurements were carried out.

Biographical Sketches

Kai Hillrichs was born in Leer (Germany) in 1990. He finished his bachelor’s and master’s degrees in the group of Prof. Dr. Andreas Schmidt at Clausthal University of Technology in 2014 and 2017, respectively. Currently he is a PhD student in the group of Andreas Schmidt working with N-heterocyclic carbenes and mesomeric betaines.

Jan C. Namyslo was born in Hannover (Germany) in 1967. He received his diploma in chemistry in 1994 from the Technische Universität Carolo-Wilhelmina zu Braunschweig, where he worked on the synthesis of analogues of the immunosuppressant FK 506 with Prof. Dr. M. E. Maier. In 1998, he obtained his Ph.D. from Clausthal University of Technology (TUC), working on asymmetric synthesis of the natural alkaloid epibatidine with Prof. Dr. D. E. Kaufmann. After this, he became responsible for the NMR department of TUC and focused on heteronuclei spectroscopy. Ongoing synthetic interest covers Pd-catalyzed pathways, highly substituted small molecules, and mechanochemical synthesis based on laboratory ball mills up to industrial-scale fluidized bed jet mills.

Felix Lederle was born in Emden (Germany) in 1989. He completed his bachelor’s and master’s degrees at the Institute of Organic Chemistry at TU Clausthal in the group of Prof. Dr. Eike Hübner. Most recently, he did research there on the synthesis of molecules in 3D-printed reaction flasks with online analytics and found his love for DFT calculations of organic molecules in this context. In 2020, he received his PhD from the same university, but at the Institute of Technical Chemistry under the supervision of Prof. Dr. Sabine Beuermann, with a thesis on PVDF block copolymers. He is currently working as a PostDoc at the Fraunhofer Heinrich Hertz Institute in Goslar (Germany), again together with Eike G. Hübner, in the field of surface processing with nano- and femtosecond laser pulses for various applications such as alkaline water electrolysis or dehydrogenation of LOHCs.

Eike G. Hübner, born in Kassel (Germany), grew up in several countries ranging from Penang/Malaysia and Singapore to Switzerland. He studied chemistry at the University of Konstanz and completed his diploma thesis under supervision of Prof. Dr. phil. Drs. h.c. H.-H. Brintzinger in the field of olefin polymerization. He worked on his PhD at the University of Konstanz and the Friedrich-Alexander University Erlangen-Nürnberg in the group of Prof. Dr. N. Burzlaff in the area of immobilized models of metalloenzymes. His postdoctoral research concentrated on the work of hybrid core-shell particles at the Forschungs­zentrum Jülich in the group of Prof. Dr. D. Richter. He started his independent research as a junior professor for organic materials at the Clausthal University of Technology and received his certifications for independent research and teaching in 2013. Since 2019, he has been research group leader at the Fraunhofer Heinrich Hertz Institute, HHI in Goslar and remains as apl. professor at the Clausthal University of Technology. His research focuses on surface functionalization, heterogeneous catalysts, and 3D-printing.

Andreas Schmidt, born in Wuppertal (Germany) in 1964, took his undergraduate degree at the Bergische­ Universität Wuppertal. He then graduated from the Rheinische Friedrich-Wilhelms-Universität Bonn in 1989, and received his PhD from the same university in 1992 where he worked with Prof. Dr. rer. nat. Dr. h.c. Heinrich Wamhoff. Following his graduate work, he moved to Greifswald to begin his independent research career in 1993 at the Ernst-Moritz-Arndt-Universität and obtained his habilitation diploma in 2000. Following postdoctoral research at Emory University (Atlanta, Georgia, USA) with Prof. Dr. Albert Padwa in 1999/2000 he returned to Germany where he is currently working as professor at Clausthal University of Technology. His principal research interests are focused on the chemistry of heterocycles and their applications. Major current themes are the chemistry of mesomeric betaines and their intersection with the compound class of N-heterocyclic carbenes, catalysis, switchable molecules, and materials chemistry.

Since the early days of organic chemistry, interest has been directed toward carbon atoms that do not meet the octet rule. Concerning N-heterocyclic carbenes (NHCs), the decarboxylation of iminocarboxylic acids (Böttinger, 1881),[1] thiazolium-2-carboxylate (Breslow, 1958),[2] 1-methylpyridinium-2-carboxylate (Hammick, 1949;[3] Quast, 1965;[4] Katritzky, 1982[5]) and imidazolium-2-carboxylates (Bausher, 1968)[6] can be termed early milestones in the development of this class of compounds. The same applies for, among others, the deprotonation of thiazolium salts (Breslow, 1958)[7] and α-eliminations from suitable precursors (Wanzlick, 1960; Öfele, 1968).[8] The remarkable development of N-heterocyclic carbenes, however, was undoubtedly triggered by the isolation of the first stable N-heterocyclic carbenes by Arduengo in 1991.[9] Numerous books, monographs, and reviews summarize syntheses, structures and applications of NHCs in metalorganic chemistry and catalysis,[10] main group element adduct formation,[11] and complex formations.[12] In addition, a review emphasizes the history of N-heterocyclic carbenes and presents a summary of the hitherto realized variety of parent heterocyclic ring systems of N-heterocyclic carbenes.[13] N-Heterocyclic carbenes can be generated by α-elimination from neutral covalent heterocycles as precursors (I)[14] and by reductive desulfurizations (II)[15] (Figure [1]). Most N-heterocyclic carbenes are formed by deprotonation of hetarenium salts (III)[16] and this is also true for N-heterocyclic carbenes of pyrazole.[17] In recent years it has been recognized that mesomeric betaines also offer a broad variety of suitable NHC precursors.[13] [18] [19] Thus, the extrusion of heterocumulenes (IV) such as CO₂ [20] and tautomerizations (V)[21] give access to neutral NHCs, whereas the deprotonation of mesomeric betaines results in the formation of anionic NHCs.[22]

Mesomeric betaines are conjugated compounds that can be represented exclusively by dipolar canonical formulae that delocalize their charges within a common π-electron system. The suitability of mesomeric betaines as precursors of N-heterocyclic carbenes depends on their structure, in combination with their type of conjugation which, vice versa, also translates into the properties of the corresponding N-heterocyclic carbenes. According to a recent classification,[23] five distinct classes of mesomeric betaines can be distinguished: (i) conjugated mesomeric betaines (CMB), including 228 different structures of mesoionic compounds, (ii) cross-conjugated (CCMB), (iii) pseudo-cross-conjugated (PCCMB), (iv) semi-conjugated (SCMB), and (v) pseudo-semi-conjugated (PSCMB) mesomeric betaines (Figure [2]). As outlined below, the three former mentioned classes proved to be versatile precursors of N-heterocyclic carbenes. The last two mentioned classes of mesomeric betaines, however, remain to be examined, as only very few examples have been described to date.

Some examples are as follows. Sydnones 1 (X = O)[24] as well as sydnone imines (X = NR)[25] and sydnone methides (X = CR₂)[26] are examples of conjugated mesomeric betaines (CMB) (Scheme [1]). For historic reasons, their five-membered representatives are called mesoionic compounds.[23] Characteristically, common atoms for the delocalization of the positive as well as negative charges exist in the canonical formulae. Sydnones and their derivatives can be deprotonated to give anionic N-heterocyclic carbenes 2, which possess a considerable π-electron density on the carbene carbon atom as a consequence of their heritage.

In cross-conjugated mesomeric betaines (CCMB) such as 3, the positive and negative charges are strictly delocalized in separated parts of the common π-electron system according­ to the rules of resonance, which translates into a π-electronic charge separation with respect to the frontier orbitals. On deprotonation, anionic N-heterocyclic carbenes 4 are formed, which possess an anionic backbone in cross-conjugation (Scheme [2]).[27]

Numerous examples of heterocumulene extrusions from pseudo-cross-conjugated mesomeric betaines (PCCMB) to generate N-heterocyclic carbenes have been reported. Thus, pyrazolium-2-carboxylates 5 decarboxylate under mild conditions to give pyrazol-3-ylidene 6 [28] (Scheme [3]). Pseudo-cross-conjugation can be identified by characteristic canonical formulae such as VI, possessing electron sextet structures without external octet stabilization, their charge distribution according to the rules of resonance with common sites for either charges (VII), and typical dipole types (VIII).[29] Thus, pseudo-cross-conjugated hetarenium-carboxylates are CO₂-adducts of normal N-heterocyclic carbenes (nNHCs, IX). The cation is joined to the anion via nodal positions of the highest occupied molecular orbital (HOMOs) (X). All betaines that fulfill these characteristics are crypto-NHCs and decarboxylate under mild conditions. Examples are imidazolium-2-carboxylates 7,[30] indazolium-3-carboxylates 8,[31] thiazolium-2-carboxylates 9,[32] pyridinium-2-carboxylates 10,[5] and quinolinium-2-carboxylates 11,[4] among others. The isomer of 5, pyrazolium-4-carboxylate does not fulfill the aforementioned requirements. This isomer belongs to the class of cross-conjugated mesomeric betaines (CCMB) and can be regarded as CO₂-adduct of a remote N-heterocyclic carbene (rNHC). Its decarboxylation requires harsh reaction conditions, which are synthetically not useful.[33]

In a continuation of our interest in the chemistry of mesomeric betaines[34] and their intersection with the substance class of N-heterocyclic carbenes[18] [19] [35] as well the chemistry of charged conjugated heterocycles,[36] we report here on new mesoionic compounds of pyrazole and their conversion into selenium adducts of N-heterocyclic carbenes.

The target mesomeric pyrazole betaines 18a–h were synthesized via a six-step reaction pathway starting from 4-nitropyrazole 12 (Scheme [4] and Scheme [5]). Thus, methylation[37] or phenylation[38] of 12 resulted in the formation of the 4-nitropyrazoles 13a,b, which were reduced according to reported procedures[38] and a patent[39] to give 4-aminopyrazoles 14a,b in excellent yields. These were successfully reacted with acid chlorides[25d] to form the corresponding amides 15a–h in satisfactory to excellent yields (Scheme [4] and Table [1]). Amide 15a was N-methylated to give 16 using methyl iodide in anhydrous THF. Quaternization was then accomplished by using Meerwein’s reagent to give the new pyrazolium salts 17a–i in good to excellent yields. On cation formation, the ¹H NMR chemical shifts of 3-H and 5-H of 15a–h shift considerably downfield. Thus, 3-H/5-H of 15a appear at δ = 7.47 ppm and δ = 7.99 ppm, respectively, and shift to δ = 8.67 ppm on methylation (17a).

The anion exchange resin Amberlite IRA-96 in its hydroxide form was used to convert the colorless to brownish salts 17a–h into golden-colored mesoionic compounds 18a–h (mesoionic imines) in good to excellent yields (Scheme [5], Table [1]). These can be represented by several canonical formulae such as 18a–hA–D, which are sometimes symbolized by the classical (but unsatisfactory)[29] representation shown. Potential tautomers such as 18a–hE–G are N-heterocyclic carbenes. In DMSO-d ₆ or MeCN-d ₃, however, no traces of the NHC tautomers were detectable in the NMR spectra at room temperature and, unfortunately, the limited solubility prevented us from recording spectra in nonpolar aprotic solvents. A similar spectroscopic behavior was observed in the case of the aforementioned mesoionic compound Nitron,[21a] which nevertheless undergoes typical NHC trapping reactions. Quinazolin-4-one imidazolium betaines,[40] purine-imidazolium betaines,[41] and imidazoliumphenolates,[42] which we examined earlier, behave similarly.

To study the effect of betaine formation on the orbitals, the highest occupied (HOMO) and lowest unoccupied molecular orbital (LUMO) of the salt 17a and of the corresponding betaine 18a were calculated (6-31G*/PBEO-d3).[43] As shown (Figure [3]) the HOMO of the salt 17a is located in the phenyl ring with very small coefficients at the oxygen atom, and the LUMO is exclusively located in the pyrazolium ring. On betaine formation, the frontier orbitals are localized in the same regions of the molecule, and this is characteristic of conjugated mesomeric betaines. Considerable atomic orbital coefficients of the HOMO are located on the aminide group while the phenyl ring is almost completely electronically decoupled with respect to the HOMO. As expected, the energies increase significantly by ΔE _HOMO = +4.98 eV and ΔE _LUMO = +4.00 eV on betaine formation. We also calculated the tautomer 18aE–G. Its HOMO shows the σ lone-pair of an N-heterocyclic carbene, whereas the LUMO is essentially located in the benzoyl substituent.

In 2016, calculated relative energies of formation (CREF) values have been introduced as an energy-based quantitative index of the ease of NHC formation from precursors by deprotonation.[44] CREF values complement other measures of σ-donor and/or π-properties of NHCs. Thus, molecular electrostatic potentials (MESP),[45] computationally derived ligand electronic parameters (CEP),[46] Tolman parameters (TEP),[47] energies of the frontier orbitals,[48] [49] calculated proton affinities,[48,50] coupling constants such as ¹ J _CH and ¹ J _CSe of precursor salts and selenium adducts, respectively,[51] and Huynh electronic parameters (HEP)[52] of Pd complexes have been introduced. A review compares these last mentioned different approaches to characterize the properties of NHCs and/or of their precursors.[53] We calculated the CREF values of the pyrazolium betaines 18a–h at the B3LYP/6-311++G** level in accordance to literature.[44a] In comparison to the CREF values of other mesomeric betaines as NHC precursors,[54] such as 1,3-dimethylimidazolium-4-olate (CREF = 0.576), 1,3-dimethylimidazolium-4-aminide (CREF = 0.557), the aforementioned 1,3-dimethyl-6-oxo-pyrimidinium-4-olate 3 (CREF = 0.547), and sydnone methides 1 (X = CR₂; CREF = 0.534),[26] these values seemed to be very promising (Table [2]). We also calculated the CREF value of the pyrazolium salt 17i, which we prepared for comparison. As expected, its value is much lower than that of the corresponding mesoionic compound 18a. Installing a delocalized negative charge into the system thus results in a shift of the CREF value by Δ(CREF) = 0.144. The CREF values of the non-symmetrically substituted pyrazolium salt 18h differ only by Δ(CREF_3-H –CREF_5-H ) = 0.001. Calculations reveal hydrogen bonds between the oxygen atom of the amide moiety with 3-H as well as 5-H. The energy of the calculated pyrazol-3-ylidene, however, is slightly lower than that of the corresponding pyrazol-5-ylidene (ΔΕ = 5 kJ/mol).

Deprotonation of the mesoionic compounds 18a–h resulted in the formation of the anionic N-heterocyclic carbenes 19a–h, which have to be represented by several canonical forms such as A–C, similar to the tautomers mentioned above (Scheme [6]).

Mesomeric structures such as 19a–hC, possessing two formal negative charges on the carbene carbon atom, are characteristic of anionic NHCs derived from mesoionic compounds and other conjugated mesomeric betaines.[26] They are reflected in considerable atomic orbital coefficients of the HOMO, which are π-orbitals, on the carbene carbon atom (Figure [4]). The characteristic NHC σ-orbital is HOMO-1 with large coefficients on the carbene carbon atom. Additional coefficients can be found on the amide nitrogen and oxygen atoms, in good agreement with the mesomeric structures. As expected, the energies of the HOMO as well as of the LUMO increase considerably, whereas the gap remains essentially unchanged in comparison to the salt 18a.

As the mesomeric betaines 18a–h are insoluble in THF-d ₈ and other low-polarity solvents, we performed base screenings applying Cs₂CO₃, LHMDS, n-BuLi and potassium tert-butanolate in MeCN-d ₃, respectively. Whereas no reaction occurred with Cs₂CO₃ and LHMDS, considerable shift changes were observed on addition of n-BuLi and potassium tert-butanolate, respectively; however, n-BuLi induced a precipitation. Due to fast 5-H→5-D exchange, unambiguous peak assignment of the carbene carbon atom C3 failed because HMBC measurements require intact C5-H groups. Nevertheless, trapping reactions of the N-heterocyclic carbenes were successful on treatment of the mesoionic compounds 17a–e,h and salt 17i with 2 equivalents of Cs₂CO₃ in anhydrous acetonitrile in the presence of 1.2 equivalents of selenium at reflux temperature. Thus, the selenones (‘selones’) 20a–e,h,i were formed (Scheme [7], Table [3]). The mesomeric betaines 17f,g did not react under these conditions. In a model reaction we also tried to trap the carbene without addition of base. Indeed, betaine 17b reacted with selenium without cesium carbonate to give the corresponding selenone, but in very low yield (17%). Methylation of the selenones with methyl iodide (1.5 equiv) in methanol led to the corresponding selenoethers 21a–e,h,i in quantitative yields within one hour. Deprotonation of 21a–e,h,i was accomplished using the anion exchange resin IRA-400 in its hydroxide form to give the new, strongly basic betaines 22a–e,h,i in quantitative yields. Thus, NMR spectra showed partial (22d,h) or even full reprotonation (22b) in DMSO-d ₆. Therefore NMR data were recorded on solutions of the salts 21a–e,h in DMSO-d ₆ in the presence of 0.1 mL of NaOD in D₂O. ²H channel NMR unambiguously proved the deprotonation of the amides. Methylation of the selenones induces downfield shifts of the ¹H NMR signals. Thus, the signal of 5-H shifted from 8.24 ppm in selenone 20a to 8.82 ppm in pyrazolium salt 22a.

The ⁷⁷Se NMR chemical shifts, summarized in Table [4], were determined in DMSO-d ₆. The shifts of the selenones were found in the range of 23.6 (20e) to 85.0 (20i) ppm. They cover a relatively wide range in comparison to the selenoethers 21a–e,h as well as to the betaines 22a–e,h. The exclusively high downfield shift of derivative 20h results from phenylation of the pyrazole ring, for 20i from methylation of the amide moiety. ⁷⁷Se shifts of selenone 22c could not be measured due to insolubility. Methylation shifts the ⁷⁷Se signals downfield by approximately 60 ppm for all derivatives, except for 22e for which Δδ is 80 ppm.

In summary, we present new mesoionic compounds of pyrazole, pyrazolium-4-aminides, which undergo reactions with selenium to give selenones via the NHC tautomers of the betaines or via the anionic N-heterocyclic carbenes formed by deprotonation. The selenones can be methylated to give selenoethers as cations or as new and unique mesomeric betaines.

Commercially available reagents and solvents were purchased and used without further purification unless otherwise stated. Thin-layer chromatography (TLC) was performed on 60 F254 silica-coated aluminum plates from Merck and visualized using UV-light. Melting points are uncorrected and were determined in an apparatus according to Dr. Tottoli (Büchi). The ¹H, ¹³C, and ⁷⁷Se NMR spectra were recorded with a Bruker Avance III 600 MHz spectrometer (at 600.35 MHz for ¹H NMR, 114.50 MHz for ⁷⁷Se, 150.97 MHz for ¹³C NMR), and a Bruker Avance 400 MHz spectrometer (at 400.18 MHz for ¹H NMR, 76.32 for ⁷⁷Se NMR, 100.63 MHz for ¹³C NMR). Multiplicities are described by using the abbreviations: s = singlet, d = doublet, t = triplet, q = quartet, and m = multiplet. Signal orientations in DEPT experiments are described as: o = no signal; + = up (CH, CH₃); – = down (CH₂). The ATR-IR spectra were measured with a Bruker Alpha in the range of 400 to 4000 cm^–1. The electrospray ionization mass spectra were measured with a Bruker Impact II mass spectrometer, spraying the samples from MeCN. All density-functional theory (DFT) calculations were carried out by using the multithreaded Firefly 8.2.0 QC package,[43a] which is partially based on the GAMESS (US)[43b] source code, running on Windows 10 Pro (Version 10.0.17763.914) (x86_64) on an 16 core AMD 2950X processor workstation. MM2 optimized structures were used as starting geometries.

Complete geometry optimizations were carried out on the implemented 6-31G* basis set and with the PBE0 density functional including D3 dispersion correction. For the calculation of CREF values the 6-311++G** basis set with the B3LYP density functional has been applied in accordance with literature.[44a] All calculated minima were proven to be true minima by the absence of imaginary frequencies. Molecular plots were obtained using Jmol 14.27.2.[43c]

N-Methyl-4-nitropyrazole (13a)

A sample of 4-nitropyrazole (5.00 g, 44.2 mmol) was dissolved in DMF (26.5 mL), then potassium carbonate (7.33 g, 53.1 mmol) was added. After the addition of methyl iodide (3.0 mL, 53.1 mmol) the reaction mixture was stirred for 16 h at room temperature. The reaction was quenched with water (20 mL) and was extracted three times with EtOAc. The combined organic layers were dried over MgSO₄ and the solvents were removed in vacuo. The crude product was finally purified by column chromatography (petroleum ether/EtOAc) and dried in vacuo.

Yield: 5.59 g (99%); white solid; mp 92–93 °C.

IR (ATR): 3113, 1505, 1422, 1400, 1311, 100, 969, 886, 819, 754, 648, 592, 548 cm^–1.

¹H NMR (CDCl₃, 400 MHz): δ = 8.12 (s, 1 H, 5-H_pyrazole), 8.01 (s, 1 H, 3-H_pyrazole), 3.96 (s, 3 H, N-Me).

¹³C NMR (CDCl₃, 100 MHz): δ = 135.9 (o), 135.8 (+), 129.2 (+), 40.2 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄H₅N₃O₂: 150.0274; found: 150.0273.

N-Phenyl-4-nitropyrazole (13b)

Samples of 4-nitropyrazole (2.00 g, 17.7 mmol), iodobenzene (1.8 mL, 17.7 mmol), copper(I) iodide (306 mg, 1.7 mmol) and potassium carbonate (4.44 g, 35.4 mmol) were dissolved in anhydrous DMF (36 mL) and heated to 110 °C overnight. The reaction mixture was poured into water and extracted with EtOAc. The combined organic layers were consecutively washed with water and brine, and then dried over MgSO­₄. The mixture was purified by column chromatography (petroleum ether/EtOAc, 40:1).

Yield: 2.178 g (65%); white solid; mp 131.4 °C.

IR (ATR): 3143, 3125, 1596, 1532, 1493, 1465, 1405, 1342, 1313, 1232, 1202, 1169, 1106, 1073, 1032, 1017, 1003, 975, 943, 909, 884, 815, 762, 746, 684, 651, 593, 567, 501, 480 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.63 (s, 1 H, 3-H_pyrazole or 5-H_pyrazole), 8.54 (s, 1 H, 3-H_pyrazole or 5-H_pyrazole), 7.99–7.90 (m, 2 H, C₆H₅), 7.60–7.51 (m, 2 H, C₆H₅), 7.48–7.41 (m, 1 H, C₆H₅).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 138.4 (o), 136.9 (+), 136.8 (o), 129.7 (+), 128.3 (+), 128.1 (+), 119.5 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₇N₃O₂: 212.0430; found: 212.0435.

N-Methyl-4-aminopyrazole (14a)

A sample of N-methyl-4-nitropyrazole (13a; 1.00 g, 7.9 mmol) was dissolved in EtOH (30 mL) and Pd/C (10 wt% on activated carbon, 400 mg) was added. The reaction mixture was reduced with hydrogen (1 bar) for 24 h at room temperature, filtered and dried in vacuo.

Yield: 0.71 g (93%); red oil; b.p. not measurable due to decomposition.

IR (ATR): 3320, 3216, 3111, 2937, 1623, 1583, 1430, 1401, 1346, 1051, 1017, 985, 819, 768, 648, 603 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 6.98 (d, J = 0.8 Hz, 1 H, 5-H_pyrazole), 6.89 (d, J = 0.8 Hz, 1 H, 3-H_pyrazole), 3.75 (s, 2 H, NH₂), 3.65 (s, 3 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 131.0 (o), 129.1 (+), 117.4 (+), 38.4 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₄H₇N₃: 150.0532; found: 150.0535.

N-Phenyl-4-aminopyrazole (14b)

A sample of N-phenyl-4-nitropyrazole (13b; 2.06 g, 10.9 mmol) was dissolved in MeOH (36 mL) and Pd/C (10 wt% on activated carbon, 363 mg) was added. The reaction mixture was reduced with hydrogen (1 bar) for 3 h at room temperature, filtered and dried in vacuo.

Yield: 1.552 g (90%); white solid; mp 96.3 °C.

IR (ATR): 3408, 3292, 3197, 3131, 3085, 3017, 1623, 1594, 1584, 1499, 1466, 1431, 1391, 1368, 1329, 1264, 1238, 1194, 1159, 1113, 1072, 1045, 1011, 953, 905, 848, 835, 757, 714, 687, 644, 606, 507, 487 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 7.69 (d, J = 0.8 Hz, 1 H, 3-H_pyrazole or 5-H_pyrazole), 7.69–7.66 (m, 2 H, C₆H₅), 7.43–7.39 (m, 2 H, C₆H₅), 7.27 (d, J = 0.8 Hz, 1 H, 3-H_pyrazole or 5-H_pyrazole), 7.18 (tt, J ₁ = 7.4 Hz, J ₂ = 1.1 Hz, 1 H, C₆H₅), 4.19 (br. s, 2 H, NH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 140.1 (o), 133.5 (o), 132.7 (+), 129.3 (+), 124.8 (+), 117.0 (+), 112.1 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₉N₃: 182.0689; found: 182.0689.

Preparation of the Amides 15a–h; General Procedure

Under a nitrogen atmosphere the corresponding amine (14a,b; 1 equiv) was dissolved in anhydrous CH₂Cl₂ (1.9 mL/1 mmol) and then the acyl chloride (1.2 equiv) was added slowly using a syringe. The mixture was cooled to –10 °C and then Et₃N (2.4 equiv), dissolved in anhydrous CH₂Cl₂ (0.6 mL/mmol educt) was added slowly. The reaction mixture was stirred for 1 h at –10 °C and then allowed to warm to room temperature. Stirring was continued for 16 h, then the reaction was quenched by addition of water (20 mL). The reaction mixture was then extracted with CH₂Cl₂ until the organic layer was colorless. The combined organic layers were dried over MgSO₄ and the solvent was removed in vacuo. The crude product was finally purified using column chromatography (EtOAc) and dried in vacuo.

N-(1-Methyl-1H-pyrazol-4-yl)benzamide (15a)

Yield: 1.29 g (91%); white solid; mp 136.4 °C.

IR (ATR): 3329, 3052, 3029, 2931, 1641, 1581, 1541, 1483, 1447, 1416, 1393, 1351, 1320, 1304, 1278, 778, 712, 692, 684, 615 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 8.63 (s, 1 H, NH), 7.99 (s, 1 H, 5-H_pyrazole), 7.85 (d, J = 7.4 Hz, 2 H, C₆H₅), 7.49–7.48 (m, 1 H, C₆H₅), 7.47 (s, 1 H, 3-H_pyrazole), 7.40–7.37 (m, 2 H, C₆H₅), 3.80 (s, 3 H, N-Me).

¹³C NMR (CDCl₃, 150 MHz): δ = 165.0 (o), 134.2 (o), 131.8 (+), 130.6 (+), 128.8 (+), 127.2 (+), 122.6 (+), 121.4 (+), 39.3 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₁₁N₃O: 224.0794; found: 224.0787.

2-Methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide (15b)

Yield: 530 mg (79%); white solid; mp 126.7 °C.

IR (ATR): 3289, 3273, 3157, 3079, 3067, 2965, 2928, 2851, 2160, 1638, 1581, 1538, 1445, 1410, 1392, 1351, 1299, 1271, 1184, 1093, 1022, 983, 904, 850, 795, 747, 718, 692, 670, 651, 633, 617, 457 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.30 (s, 1 H, NH), 7.99 (s, 1 H, 5-H_pyrazole), 7.49–7.47 (m, 1 H, 3-H_pyrazole), 7.44–7.40 (m, 1 H, C₆H₅), 7.39–7.34 (m, 1 H, C₆H₅), 7.30–7.25 (m, 2 H, C₆H₅), 3.82 (s, 3 H, N-Me), 2.37 (s, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 166.0 (o), 136.6 (o), 135.5 (o), 130.6 (+), 129.9 (+), 129.6 (+), 127.1 (+), 125.6 (+), 121.7 (o), 121.4 (+), 38.6 (+), 19.4 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₃N₃O: 238.0951; found: 238.0951.

N-(1-Methyl-1H-pyrazol-4-yl)cyclopropanecarboxamide (15c)

Yield: 701 mg (61%); white solid; mp 120.2 °C.

IR (ATR): 3203, 3132, 3091, 2994, 2929, 2906, 1643, 1583, 1559, 1446, 1410, 1378, 1347, 1225, 1159, 1021, 982, 950, 884, 828, 797, 753, 692, 650, 622 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.11 (s, 1 H, NH), 7.80 (s, 1 H, 5-H_pyrazole), 7.37 (d, J = 0.7 Hz, 1 H, 3-H_pyrazole), 3.76 (s, 3 H, N-Me), 1.68–1.63 (m, 1 H, CH), 0.77–0.71 (m, 4 H, CH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 169.8 (o), 129.4 (+), 121.9 (o), 121.0 (+), 38.6 (+), 13.8 (+). 6.7 (–).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₁N₃O: 188.0794; found: 188.0798.

N-(1-Methyl-1H-pyrazol-4-yl)propionamide (15d)

Yield: 351 mg (32%); white solid; mp 95.8 °C.

IR (ATR): 3341, 3296, 3144, 3061, 2982, 2945, 2886, 1685, 1654, 1605, 1591, 1556, 1508, 1455, 1414, 1407, 1380, 1233, 1215, 1168, 1052, 1012, 952, 927, 872, 842, 823, 806, 784, 652, 521 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.81 (s, 1 H, NH), 7.83 (d, J = 0.6 Hz, 1 H, 5-H_pyrazole), 7.36 (d, J = 0.6 Hz, 1 H, 3-H_pyrazole), 3.76 (s, 3 H, N-Me), 2.23 (q, J = 7.6 Hz, 2 H, CH₂), 1.05 (t, J = 7.6 Hz, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 9.8 (+, 1C, C-10), 28.6 (–, 1C, C-9), 38.6 (+, 1C, C-6), 121.1 (+, 1C, C-5), 121.8 (o, 1C, C-4), 129.5 (+, 1C, C-3), 170.2 (o, 1C, C-8).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₇H₁₁N₃O: 176.0794; found: 176.0785.

1,1-Diethyl-3-(1-methyl-1H-pyrazol-4-yl)urea (15e)

Yield: 619 mg (46%); brownish solid; mp 246.2 °C.

IR (ATR): 3433, 3351, 3248, 3176, 3150, 3102, 2970, 2935, 2194, 1634, 1582, 1564, 1495, 1442, 1422, 1379, 1343, 1278, 1180, 1159, 1087, 1018, 977, 831, 771, 655, 617 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.16 (s, 1 H, NH), 7.65 (s, 1 H, 5-H_pyrazole), 7.33 (s, 1 H, 3-H_pyrazole), 3.73 (s, 3 H, N-Me), 3.27 (q, J = 7.0 Hz, 4 H, CH₂), 1.05 (t, J = 7.0 Hz, 6 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 154.0 (o), 129.9 (+), 123.5 (o), 120.6 (+), 40.4 (–), 38.5 (+), 13.9 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₆N₄O: 219.1216; found: 219.1220.

N-(1-Methyl-1H-pyrazol-4-yl)-3,5-bis(trifluoromethyl)benzamide (15f)

Yield: 2.184 g (91%); white solid; mp 206.5 °C.

IR (ATR): 3316, 3183, 3120, 2944, 1861, 1840, 1647, 1624, 1589, 1566, 1468, 1446, 1404, 1375, 1338, 1273, 1169, 1144, 1124, 1021, 984, 934, 911, 844, 819, 746, 700, 680, 656, 575, 444 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.86 (s, 1 H, NH), 8.58 (s, 2 H, C₆H₃), 8.33 (s, 1 H, C₆H₃), 8.06 (s, 1 H, 5-H_pyrazole), 7.60 (d, J = 0.5 Hz, 1 H, 3-H_pyrazuole), 3.84 (s, 3 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 160.3 (o), 136.3 (o), 130.6 (q, J = 33.2 Hz, o), 130.3 (+), 128.2 (q, J = 2.9 Hz, +), 124.9 (q, J = 3.4 Hz, +), 123.1 (q, J = 272.8 Hz, o), 122.0 (+), 121.1 (o), 38.8 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₉F₆N₃O: 360.0542; found: 360.0536.

N-(1-Methyl-1H-pyrazol-4-yl)-3,5-dinitrobenzamide (15g)

Yield: 741 mg (35%); yellow solid; mp 211.2 °C.

IR (ATR): 3253, 3239, 3184, 3146, 3091, 3069, 2998, 2945, 2873, 1860, 1669, 1625, 1592, 1537, 1396, 1339, 1286, 1251, 1188, 1148, 1078, 1023, 994, 932, 916, 827, 805, 729, 711, 651, 618, 490, 465, 446 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.05 (s, 1 H, NH), 9.13 (d, J = 2.1 Hz, 2 H, C₆H₃), 8.95 (t, J = 2.1 Hz, 1 H, C₆H₃), 8.05 (s, 1 H, 5-H_pyrazole), 7.59 (d, J = 0.7 Hz, 1 H, 3-H_pyrazole), 3.84 (s, 3 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 159.0 (o), 148.2 (o), 136.6 (o), 130.2 (+), 127.6 (+), 122.1 (+), 121.0 (o), 120.9 (+), 38.8 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₁H₉N₅O₅: 314.0496; found: 314.0499.

N-(1-Phenyl-1H-pyrazol-4-yl)-benzamide (15h)

Yield: 2.152 g (89%); brown solid; mp 170.2 °C.

IR (ATR): 3270, 3155, 3103, 3050, 2849, 2650, 1943, 1637, 1597, 1586, 1557, 1502, 1489, 1447, 1398, 1363, 1328, 1287, 1254, 1217, 1177, 1166, 1152, 1127, 1103, 1073, 1043, 1024, 1015, 945, 925, 902, 855, 833, 797, 780, 770, 753, 709, 685, 664, 653, 612, 517, 504, 467, 425 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.66 (s, 1 H, NH), 8.71 (d, J = 0.4 Hz, 1 H, 5-H_pyrazole), 8.02–7.98 (m, 2 H, C₆H₅), 7.94 (d, J = 0.4 Hz, 1 H, 3-H_pyrazole), 7.84–7.81 (m, 2 H, N-C₆H₅), 7.61–7.58 (m, 1 H, C₆H₅), 7.57–7.53 (m, 2 H, C₆H₅), 7.52–7.47 (m, 2 H, N-C₆H₅), 7.30 (tt, J ₁ = 7.4 Hz, J ₂ = 1.1 Hz, 1 H, N-C₆H₅).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 163.9 (o), 139.7 (o), 133.9 (o), 133.4 (+), 131.6 (+), 129.6 (+), 128.5 (+), 127.4 (+), 126.0 (+), 124.1 (o), 118.0 (+), 117.7 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₆H₁₃N₃O: 286.0951; found: 286.0950.

N-Methyl-N-(1-methyl-1H-pyrazol-4-yl)benzamide (16)

Under a nitrogen atmosphere, 15a (935 mg, 4.6 mmol) was dissolved in anhydrous THF (15 mL) and a solution of LHMDS (2 mol/L in THF, 2.8 mL, 5.6 mmol) was added dropwise. The mixture was stirred at room temperature for 3 hours and then methyl iodide (0.33 mL, 5.6 mmol) was added. The mixture was stirred for 16 hours and then extracted with EtOAc. The combined organic layers were dried over MgSO­₄ and dried in vacuo. The crude product was finally purified by column chromatography (petroleum ether/EtOAc) and dried in vacuo.

Yield: 859 mg (87%); white solid; mp 82.7 °C.

IR (ATR): 3169, 3050, 2980, 2933, 1911, 1828, 1729, 1624, 1599, 1564, 1473, 1448, 1410, 1397, 1379, 1329, 1202, 1175, 1127, 1102, 1082, 1054, 1022, 985, 932, 829, 794, 783, 729, 700, 658, 643, 626, 459 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 7.66 (s, 1 H, 5-H_pyrazole), 7.42–7.32 (m, 5 H, C₆H₅), 7.29 (s, 1 H, 3-H_pyrazole), 3.72 (s, 3 H, N₁-CH₃), 3.27 (s, 3 H, N_amide-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 169.8 (o), 137.2 (o), 134.2 (+), 129.7 (+), 128.3 (+), 127.9 (+), 127.6 (o), 125.7 (+), 39.2 (+), 38.7 (+).

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₃N₃O⁺: 238.0951; found: 238.0965.

Preparation of Salts 17a–i; General Procedure

Under a nitrogen atmosphere amide 15a–h or 16 (1 equiv) was dissolved in anhydrous CH₂Cl₂ and Meerwein’s reagent (Me₃OBF₄; 1.2 equiv), dissolved in anhydrous CH₂Cl₂, were added slowly using a syringe. The mixture was stirred at room temperature for 48 h. Then, ice-cold Et₂O (25 mL) was added. The precipitated solid was filtered off and washed subsequently with ice-cold ether and EtOAc. The product was finally dried in vacuo.

4-Benzamido-1,2-dimethyl-1H-pyrazolium Tetrafluoroborate (17a)

Yield: 2.219 g (7.3 mmol, 96%); white solid; mp 244.2 °C.

IR (ATR): 3364, 3155, 3067, 3044, 1660, 1602, 1566, 1493, 1456, 1416, 1377, 1285, 1161, 1058, 1026, 1017, 896, 867, 837, 799, 710, 688, 629, 505 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.00 (s, 1 H, NH), 8.67 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 7.98–7.96 (m, 2 H, C₆H₅), 7.66–7.63 (m, 1 H, C₆H₅), 7.59–7.56 (m, 2 H, C₆H₅), 4.12 (s, 6 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 164.4 (o), 132.9 (o), 132.3 (+), 128.7 (+), 127.7 (+), 127.6 (+), 121.5 (o), 36.4 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₂H₁₄N₃O⁺: 216.1131; found: 216.1132.

1,2-Dimethyl-4-(2-methylbenzamido)-1H-pyrazolium Tetra­fluoroborate (17b)

Yield: 408 mg (81%); white solid; mp 116.2 °C.

IR (ATR): 3563, 3355, 3178, 3142, 3040, 2973, 2938, 1666, 1605, 1558, 1451, 1412, 1377, 1302, 1262, 1057, 1024, 1009, 957, 897, 832, 799, 743, 661, 625, 610, 522 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.95 (s, 1 H, NH), 8.64 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 7.53–7.47 (m, 1 H, C₆H₄), 7.47–7.42 (m, 1 H, C₆H₄), 7.36–7.31 (m, 2 H, C₆H₄), 4.11 (s, 6 H, N-Me), 2.39 (s, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 167.0 (o), 135.9 (+), 135.0 (o), 130.9 (+), 130.5 (+), 127.5 (+), 127.3 (+), 125.8 (+), 121.3 (o), 36.4 (+), 19.4 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₃H₁₆N₃O⁺: 230.1288; found: 230.1286.

4-(Cyclopropanecarboxamido)-1,2-dimethyl-1H-pyrazolium Tetrafluoroborate (17c)

Yield: 868 mg (93%); white solid; mp 149.9 °C.

IR (ATR): 3335, 3140, 3105, 3055, 3038, 1673, 1605, 1557, 1507, 1455, 1421, 1373, 1242, 1201, 1164, 1052, 1013, 954, 891, 845, 828, 634, 521 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.76 (s, 1 H, NH), 8.49 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.06 (s, 6 H, N-Me), 1.73–1.69 (m, 1 H, CH), 0.87–0.80 (m, 4 H, CH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 171.4 (o), 127.1 (+), 121.4 (o), 36.3 (+), 13.9 (+), 7.6 (–).

HRMS (ESI): m/z [M]⁺ calcd for C₉H₁₄N₃O⁺: 180.1131; found: 180.1137.

1,2-Dimethyl-4-propionamido-1H-pyrazolium Tetrafluoroborate (17d)

Yield: 390 mg (72%); white solid; mp 137.8 °C.

IR (ATR): 3340, 3144, 2983, 2946, 1685, 1605, 1558, 1509, 1455, 1416, 1407, 1380, 1245, 1212, 1168, 1112, 1053, 1014, 926, 872, 841, 823, 807, 767, 665, 635, 610, 592, 568, 521, 491 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.44 (s, 1 H, NH), 8.49 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.06 (s, 6 H, N-Me), 2.32 (q, J = 7.6 Hz, 2 H, CH₂), 1.08 (t, J = 7.6 Hz, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 171.7 (o), 127.1 (+), 121.4 (o), 36.3 (+), 28.6 (–), 9.4 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₈H₁₄N₃O⁺: 168.1131; found: 168.1125.

4-(3,3-Diethylureido)-1,2-dimethyl-1H-pyrazolium Tetrafluoro­borate (17e)

Yield: 521 mg (75%); brownish solid; mp 191.5 °C.

IR (ATR): 3376, 3149, 2994, 2983, 2946, 1641, 1603, 1559, 1495, 1452, 1428, 1403, 1366, 1309, 1272, 1222, 1160, 1051, 1010, 866, 831, 790, 766, 620, 521 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.86 (s, 1 H, NH), 8.35 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.05 (s, 6 H, N-Me), 3.30 (q, J = 7.0 Hz, 4 H, CH₂), 1.08 (t, J = 7.0 Hz, 6 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 153.5 (o), 126.7 (+), 123.6 (o), 40.6 (–), 36.2 (+), 13.8 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₀H₁₉N₄O⁺: 211.1553; found: 211.1558.

4-(3,5-Bis(trifluoromethyl)benzamido)-1,2-dimethyl-1H-pyrazolium Tetrafluoroborate (17f)

Yield: 2.082 g (80%); white solid; mp 205.7 °C.

IR (ATR): 3355, 3172, 3124, 3089, 3054, 1687, 1610, 1569, 1515, 1458, 1425, 1382, 1269, 1175, 1141, 1068, 1009, 928, 913, 847, 832, 776, 712, 698, 682, 632, 570, 522, 442 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.39 (s, 1 H, NH), 8.70 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 8.58 (s, 2 H, C₆H₃), 8.43 (s, 1 H, C₆H₃), 4.15 (s, 6 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 161.8 (o), 135.3 (o), 130.7 (q, J = 33.4 Hz, o), 128.4 (q, J = 2.7 Hz, +), 128.0 (+), 125.8 (q, J = 3.7 Hz, +), 123.0 (q, J = 272.9 Hz, o), 120.8 (o), 36.6 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₂F₆N₃O⁺: 352.0879; found: 352.0872.

4-(3,5-Dinitrobenzamido)-1,2-dimethyl-1H-pyrazolium Tetra­fluoroborate (17g)

Yield: 0.711 g (88%); white solid; mp 223.2 °C

IR (ATR): 335, 3157, 3095, 1688, 1629, 1608, 1567, 1531, 1454, 1416, 1382, 1346, 1283, 1247, 1229, 1150, 1065, 1027, 992, 943, 919, 838, 746, 730, 719, 660, 636, 624, 522, 450 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.61 (s, 1 H, NH), 9.13 (d, J = 2.1 Hz, 2 H, C₆H₃), 9.04 (t, J = 2.1 Hz, 1 H, C₆H₃), 8.74 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.16 (s, 6 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 160.6 (o), 148.3 (o), 135.5 (o), 128.1 (+), 127.9 (+), 121.7 (+), 120.7 (o), 36.6 (+).

HR-MS (ESI): m/z [M]⁺ calcd for C₁₂H₁₂N₅O₅ ⁺: 306.0833; found: 306.0853.

4-Benzamido-2-methyl-1-phenyl-1H-pyrazolium Tetrafluoro­borate (17h)

Yield: 1.290 g (93%); white solid; mp 206.2 °C.

IR (ATR): 3362, 3161, 3122, 1662, 1609, 1580, 1560, 1509, 1491, 1466, 1451, 1422, 1392, 1366, 1282, 1210, 1192, 1166, 1071, 1034, 1010, 990, 634, 923, 895, 848, 798, 762, 718, 704, 688, 668, 643, 622, 589, 557, 520, 488, 448, 431 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 11.19 (s, 1 H, NH), 9.06 (d, J = 1.0 Hz, 1 H, 3-H_pyrazole), 8.82 (d, J = 1.0 Hz, 1 H, 5-H_pyrazole), 8.03–7.99 (m, 2 H, C₆H₅), 7.82–7.79 (m, 2 H, N₁-C₆H₅), 7.79–7.76 (m, 1 H, N₁-C₆H₅), 7.75–7.71 (m, 2 H, N₁-C₆H₅), 7.68–7.65 (m, 1 H, C₆H₅), 7.62–7.58 (m, 2 H, C₆H₅), 3.94 (s, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 164.8 (o), 132.8 (o), 132.52 (o), 132.46 (+), 132.2 (+), 130.1 (+), 128.8 (+), 128.2 (+), 127.9 (+), 127.6 (+), 122.5 (o), 37.6 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₇H₁₆N₃O⁺: 278.1288; found: 278.1298.

1,2-Dimethyl-4-(N-merthylbenzamido)-1H-pyrazolium Tetra­fluoroborate (17i)

Yield: 1.276 g (90%); white solid; mp 91.4 °C.

IR (ATR): 3173, 3131, 1716, 1634, 1593, 1575, 1529, 1494, 1476, 1452, 1406, 1393, 1360, 1321, 1287, 1253, 1214, 1197, 1184, 1021, 993, 840, 816, 801, 767, 738, 726, 707, 655, 624, 594, 521, 499, 409 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.80 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 7.58–7.45 (m, 5 H, C₆H₅), 4.11 (s, 6 H, N₁-Me, N₂-Me), 3.29 (s, 3 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 169.4 (o), 134.8 (o), 130.5 (+), 128.5 (+), 127.5 (+), 125.6 (o), 122.6 (+), 38.2 (+), 36.6 (+).

HRMS (ESI): m/z [M]⁺ calcd for C₁₃H₁₆N₃O⁺: 230.1288; found: 230.1282.

NMR assignment not possible due to broadened signals in the ¹H NMR spectra.

Preparation of the Betaines 18a–h; General Procedure

Salt 17a–h was dissolved in a mixture of distilled water and MeOH (1:1) and added dropwise on an ion-exchange-column charged with Amberlite IR 96 in its hydroxide form. The product was collected, the solvent mixture was distilled off in vacuo, and the product was dried in vacuo.

Benzoyl-(1,2-dimethyl-1H-pyrazolium-4-yl)amide (18a)

Yield: 337 mg (95%); golden solid; mp 209.8 °C.

IR (ATR): 3347, 3155, 3091, 3034, 2952, 1655, 1603, 1561, 1532, 1491, 1446, 1375, 1284, 1222, 1174, 1158, 1108, 1074, 1055, 1026, 893, 820, 804, 701, 623 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.73 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 8.10 (d, J = 7.3 Hz, 2 H, C₆H₅), 7.48–7.44 (m, 1 H, C₆H₅), 7.44–7.37 (m, 2 H, C₆H₅), 4.06 (s, 6 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 165.9 (o), 136.0 (o), 130.6 (+), 128.6 (+), 127.90 (+), 127.88 (+), 126.9 (o), 36.1 (+).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₃N₃O: 216.1131; found: 216.1134.

(1,2-Dimethyl-1H-pyrazolium-4-yl)(2-methylbenzoyl)amide (18b)

Yield: 193 mg (93%); golden solid; mp 118.3 °C.

IR (ATR): 3376, 3127, 3024, 2943, 1652, 1599, 1558, 1532, 1447, 1398, 1374, 1303, 1276, 1224, 1160, 1137, 1093, 1046, 823, 783, 736, 626, 454 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.63 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 7.52–7.49 (m, 1 H, C₆H₄), 7.28–7.24 (m, 1 H, C₆H₄), 7.20–7.15 (m, 2 H, C₆H₄), 4.06 (s, 6 H, N-Me), 2.38 (s, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 169.1 (o), 138.4 (o), 135.6 (o), 130.3 (+), 128.6 (+), 128.5 (+), 127.8 (+), 127.3 (o), 125.1 (+), 36.0 (+), 20.0 (+).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅N₃O: 230.1288; found: 230.1287.

Cyclopropanecarbonyl(1,2-dimethyl-1H-pyrazolium-4-yl)amide (18c)

Yield: 511 mg (95%); golden solid; mp 136.2 °C.

IR (ATR): 3158, 3081, 3011, 2952, 2931, 2782, 1670, 1606, 1566, 1450, 1419, 1372, 1235, 1196, 1156, 1051, 1035, 950, 822, 628 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.52 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.03 (s, 6 H, N-Me), 1.81–1.72 (, 1 H, CH), 0.72–0.63 (m, 4 H, CH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 171.9 (o), 127.4 (+), 123.0 (o), 36.2 (+), 13.9 (+), 7.2 (–).

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₃N₃O: 180.1131; found: 180.1135.

(1,2-Dimethyl-1H-pyrazolium-4-yl)(propionyl)amide (18d)

Yield: 234 mg (99%); golden solid; mp 136.2 °C.

IR (ATR): 3342, 3286, 3246, 3144, 3044, 3029, 2984, 2947, 2912, 2824, 2784, 2734, 1681, 1605, 1568, 1453, 1407, 1376, 1338, 1222, 1165, 1157, 1072, 1062, 1004, 920, 888, 827, 769, 640, 564, 492 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.51 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 3.03 (s, 6 H, N-Me), 2.22 (q, J = 7.6 Hz, 2 H, CH₂), 1.03 (t, J = 7.6 Hz, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 173.4 (o), 127.9 (+), 126.6 (o), 36.0 (+), 29.7 (–), 10.3 (+).

HRMS (ESI): m/z [M + H]⁺ calcd for C₈H₁₃N₃O: 168.1131; found: 168.1120.

(1,2-Dimethyl-1H-pyrazolium-4-yl)(propionyl)amide (18e)

Yield: 325 mg (97%); golden solid; mp 75.0 °C.

IR (ATR): 3368, 3284, 3247, 3145, 2976, 2933, 2875, 1634, 1600, 1564, 1486, 1448, 1427, 1402, 1361, 1347, 1276, 1221, 1159, 1096, 1055, 1016, 630 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.47 (s, 2 H, 3-H_pyrazole, 5-H_pyrazole), 4.02 (s, 6 H, N-Me), 3.32 (q, J = 7.0 Hz, 4 H, CH₂), 1.04 (t, J = 7.0 Hz, 6 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 154.9 (o), 126.9 (+), 125.9 (o), 40.4 (–), 36.0 (+), 13.9 (+).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₈N₄O: 211.1553; found: 211.1561.

(3,5-Bis(trifluoromethyl)benzoyl)(1,2-dimethyl-1H-pyrazolium-4-yl)amide (18f)

Yield: 1.204 g (75%); golden solid; mp 163.8 °C.

IR (ATR): 3359, 3333, 3322, 3127, 3113, 2949, 1680, 1645, 1608, 1544, 1449, 1403, 1372, 1319, 1275, 1167, 1119, 1050, 1023, 1005, 900, 844, 832, 772, 756, 701, 681, 656, 628, 605, 582, 499 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.57 (m, 4 H, 3-H_pyrazole, 5-H_pyrazole, C₆H₃), 8.15 (m, 1 H, C₆H₃), 4.07 (s, 6 H, N-Me).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 163.4 (o), 140.7 (o), 129.9 (q, J = 32.7 Hz, o), 129.3 (+), 129.2 (o), 128.1 (q, J = 2.8 Hz, +), 123.4 (q, J = 272.7 Hz, o), 123.1 (q, J = 3.4 Hz, +), 36.0 (+).

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₁F₆N₃O: 352.0879; found: 352.0885.

(1,2-Dimethyl-1H-pyrazolium-4-yl)(3,5-dinitrobenzoyl)amide (18g)

Yield: 447 mg (97%); orange solid; mp 106.0 °C.

IR (ATR): 3428, 3167, 3122, 3093, 3016, 2943, 2864, 1623, 1598, 1561, 1526, 1482, 1445, 1394, 1377, 1343, 1276, 1225, 1160, 1134, 1072, 1049, 1013, 944, 921, 908, 833, 817, 722, 656, 630, 591, 574, 528, 503, 470 cm^–1.

Due to the insolubility of the compound, no NMR spectra could be measured.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₂H₁₁N₅O₅: 306.0833; found: 306.0834.

N-Benzoyl-(2-methyl-1-phenyl-1H-pyrazolium-4-yl)amide (18h)

Yield: 876 mg (96%); golden solid; mp 197.7 °C

IR (ATR): 3177, 3063, 3025, 2196, 1669, 1602, 1561, 1524, 1493, 1449, 1422, 1382, 1280, 1191, 1161, 1105, 1066, 1029, 1009, 932, 895, 841, 819, 798, 786, 765, 693, 667, 616, 556, 502, 488, 461 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.13 (s, 1 H, 3-H_pyrazole), 8.94 (s, 1 H, 5-H_pyrazole), 8.17–8.11 (m, 2 H, C₆H₅), 7.78–7.74 (m, 2 H, N₁-C₆H₅), 7.74–7.71 (m, 1 H, N₁-C₆H₅), 7.71–7.66 (m, 2 H, N₁-C₆H₅), 7.51–7.45 (m, 1 H, C₆H₅), 7.45–7.38 (m, 2 H, C₆H₅), 3.89 (s, 3 H, N₂-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 166.2 (o), 136.0 (o), 132.9 (o), 131.7 (+), 131.2 (+), 130.7 (+), 130.1 (+), 129.1 (+), 128.2 (o), 128.0 (+), 127.6 (+), 37.3 (+).

HRMS (ESI): m/z [M – H]⁺ calcd for C₁₇H₁₅N₃O: 278.1288; found: 278.1279.

Preparation of the Selenones 20a–e,h,i; General Procedure

Under a nitrogen atmosphere, the corresponding betaine 18a–e,h (1 equiv), salt 16 (1 equiv), and selenium (1.2 equiv) were dissolved in anhydrous acetonitrile, then cesium carbonate (2 equiv) was added. The mixture was stirred under reflux for 7 hours. The solvent was distilled off in vacuo and the crude reaction mixture was finally purified by chromatography (dichloromethane/MeOH, 18:1). The products were dried in vacuo.

N-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)­benzamide (20a)

Yield: 86 mg (63%); white solid; mp 226.9 °C.

IR (ATR): 3332, 3166, 3132, 3023, 2926, 1731, 1653, 1582, 1526, 1498, 1478, 1402, 1390, 1373, 1340, 1298, 1263, 1205, 1183, 1155, 1120, 1094, 1071, 1040, 1022, 1001, 970, 923, 902, 870, 835, 797, 702, 684, 666, 625, 580, 545, 435 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 8.84 (s, 1 H, NH), 8.24 (s, 1 H, 5-H_pyrazole), 7.95 (d, J = 7.6 Hz, 2 H, C₆H₅), 7.56–7.52 (m, 1 H, C₆H₅), 7.51–7.46 (m, 2 H, C₆H₅), 4.00 (s, 3 H, N₂-CH₃), 3.81 (s, 3 H, N₁-CH₃).

¹³C NMR (CDCl₃, 150 MHz): δ = 164.6 (o), 151.1 (o), 133.1 (o), 132.2 (+), 128.9 (+), 127.3 (+), 125.3 (o), 124.4 (+), 36.8 (+), 34.0 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 38.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₂H₁₃N₃OSe: 318.0116; found: 318.0118.

N-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)-2-methylbenzamide (20b)

Yield: 316 mg (47%); yellow solid; mp 131.2 °C.

IR (ATR): 3388, 2989, 2923, 1661, 1600, 1574, 1523, 1483, 1434, 1406, 1390, 1293, 1262, 1204, 1162, 1136, 1101, 1074, 1041, 905, 847, 787, 741, 689, 648, 627, 584, 560, 503, 455 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 8.43 (s, 1 H, NH), 8.28 (s, 1 H, 5-H_pyrazole), 7.59 (d, J = 7.7 Hz, 1 H, C₆H₄), 7.40–7.34 (m, 1 H, C₆H₄), 7.30–7.23 (m, 2 H, C₆H₄), 4.02 (s, 3 H, N₂-CH₃), 3.81 (s, 3 H, N₁-CH₃), 2.52 (s, 3 H, CH₃).

¹³C NMR (CDCl₃, 150 MHz): δ = 167.4 (o), 151.3 (o), 137.0 (o), 134.7 (o), 131.5 (+), 130.8 (+), 127.6 (+), 126.2 (+), 125.5 (o), 124.5 (+), 36.8 (+), 34.0 (+), 20.4 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 39.1.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₅N₃OSe: 332.0273; found: 332.0271.

N-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)-cyclopropanecarboxamide (20c)

Yield: 215 mg (36%); yellow solid; mp 242.7 °C.

IR (ATR): 3243, 3165, 3092, 3015, 2961, 2918, 2850, 1729, 1652, 1571, 1525, 1492, 1455, 1429, 1399, 1372, 1327, 1262, 1212, 1197, 1177, 1153, 1096, 1078, 1062, 1046, 1035, 948, 887, 843, 821, 794, 742, 700, 671, 633, 542, 532, 478 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 8.22 (s, 1 H, NH), 8.08 (s, 1 H, 5-H_pyrazole), 4.01 (s, 3 H, N₂-CH₃), 3.77 (s, 3 H, N₁-CH₃), 1.71–1.66 (m, 1 H, CH), 1.05–1.01 (m, 2 H, CH₂), 0.90–0.85 (m, 2 H, CH₂).

¹³C NMR (CDCl₃, 150 MHz): δ = 171.7 (o), 150.4 (o), 125.7 (o), 124.5 (+), 36.8 (+), 34.0 (+), 15.2 (+), 8.3 (–).

⁷⁷Se NMR: not detected.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₉H₁₃N₃OSe: 282.0116; found: 282.0110.

N-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)-propionamide (20d)

Yield: 133 mg (60%); yellow solid; mp 173.9 °C.

IR (ATR): 3318, 3135, 3022, 2979, 2963, 2928, 1661, 1588, 1525, 1484, 1443, 1406, 1388, 1370, 1323, 1262, 1225, 1182, 1156, 1102, 1072, 1045, 1009, 925, 842, 809, 717, 668, 607, 559, 541 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 8.10 (s, 1 H, 5-H_pyrazole), 7.99 (br. s, 1 H, NH), 3.97 (s, 3 H, N₂-CH₃), 3.78 (s, 3 H, N₁-CH₃), 2.42 (q, J = 7.6 Hz, 2 H, CH₂), 1.21 (t, J = 7.6 Hz, 3 H, CH₃).

¹³C NMR (CDCl₃, 150 MHz): δ = 171.7 (o), 149.9 (o), 125.2 (o), 124.4 (+), 36.8 (+), 34.0 (+), 29.8 (–), 9.6 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 56.2.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₈H₁₃N₃OSe: 270.0116; found: 270.0117.

3-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)-1,1-diethylurea (20e)

Yield: 165 mg (60%); white solid; mp 154.4 °C.

IR (ATR): 3318, 3119, 2976, 2931, 2872, 1638, 1589, 1526, 1479, 1446, 1416, 1402, 1376, 1362, 1331, 1310, 1262, 1215, 1158, 1093, 1078, 1064, 1030, 970, 927, 869, 835, 787, 776, 752, 650, 618, 554, 830, 493, 451, 408 cm^–1.

¹H NMR (CDCl₃, 600 MHz): δ = 7.86 (s, 1 H, 5-H_pyrazole), 7.33 (br. s, 1 H, NH), 3.96 (s, 3 H, N₂-CH₃), 3.74 (s, 3 H, N₁-CH₃), 3.37 (q, J = 7.2 Hz, 4 H, 11-H, CH₂), 1.22 (t, J = 7.2 Hz, 6 H, CH₃).

¹³C NMR (CDCl₃, 150 MHz): δ = 154.1 (o), 149.0 (o), 127.1 (o), 123.1 (+), 41.8 (–), 36.8 (+), 34.1 (+), 13.9 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 23.6.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₀H₁₈N₄OSe: 313.0538; found: 313.0546.

N-(2-Methyl-1-phenyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)benzamide (20h)

Yield: 95 mg (25%); yellow solid; mp 175.8 °C.

IR (ATR): 3300, 3054, 3253, 2198, 1653, 1592, 1578, 1538, 1487, 1457, 1443, 1403, 1372, 1355, 1300, 1263, 1211, 1162, 1098, 1073, 1039, 1025, 1001, 901, 826, 812, 794, 758, 693, 686, 638, 564, 537, 479, 440 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.05 (s, 1 H, NH), 8.52 (s, 1 H, 5-H_pyrazole), 7.96–7.92 (m, 2 H, C₆H₅), 7.70–7.66 (m, 2 H, N₁-C₆H₅), 7.66–7.62 (m, 4 H, C₆H₅, N₁-C₆H₅), 7.62–7.58 (m, 2 H, C₆H₅), 3.77 (s, 3 H, N₂-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 163.4 (o), 152.9 (o), 134.8 (o), 132.9 (o), 132.2 (+), 130.4 (+), 130.0 (+), 129.0 (+), 127.0 (+), 126.9 (+), 124.7 (+), 124.6 (o), 35.4 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 77.7.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₇H₁₅N₃OSe: 380.0273; found: 380.0270.

N-(1,2-Dimethyl-3-selenoxo-2,3-dihydro-1H-pyrazol-4-yl)-N-methylbenzamide (20i)

Yield: 68 mg (70%); orange solid; mp 182.6 °C.

IR (ATR): 3309, 3133, 3070, 2960, 2923, 2852, 1634, 1599, 1568, 1505, 1444, 1412, 1403, 1386, 1344, 1260, 1229, 1200, 1178, 1157, 1118, 1097, 1070, 1052, 1023, 987, 917, 870, 857, 786, 759, 739, 702, 667, 653, 615, 578, 562, 466, 440 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 7.85 (s, 1 H, 5-H_pyrazole), 7.45 (d, 2 H, J = 7.4 Hz, C₆H₅), 7.32–7.27 (m, 1 H, C₆H₅), 7.27–7.20 (m, 2 H, C₆H₅), 3.85 (s, 3 H, N₂-CH₃), 3.72 (s, 3 H, N₁-CH₃), 3.19 (s, 3 H, N₃-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 170.5 (o), 155.6 (o), 136.1 (o), 132.6 (+), 129.6 (+), 129.3 (o), 127.6 (+), 127.3 (+), 36.5 (+), 35.5 (+), 33.6 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 85.0.

HRMS (ESI): m/z [M + Na]⁺ calcd for C₁₃H₁₅N₃OSe: 332.0273; found: 332.0274.

Preparation of the Selenoethers 21a–e,h,i; General Procedure

Samples of selenone 20a–e,h (1 equiv) was dissolved in MeOH and then treated dropwise with methyl iodide (1.5 equiv) using a syringe. The mixture was stirred for 1 h at room temperature. After the solvent was distilled off in vacuo, the products were dried in vacuo without further purification.

4-Benzamido-1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium Iodide (21a)

Yield: 44 mg (99%); yellow solid; mp 198.4 °C.

IR (ATR): 3259, 3154, 3086, 2988, 2921, 1665, 1579, 1537, 1502, 1486, 1448, 1437, 1424, 1405, 1382, 1360, 1303, 1269, 1202, 1161, 1120, 1100, 1070, 1021, 999, 976, 933, 914, 898, 868, 840, 799, 703, 687, 666, 645, 625, 539, 431 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.32 (s, 1 H, NH), 8.82 (s, 1 H, 5-H_pyrazole), 8.00–7.96 (m, 2 H, C₆H₅), 7.67–7.63 (m, 1 H, C₆H₅), 7.60–7.55 (m, 2 H, C₆H₅), 4.22 (s, 3 H, N₁-CH₃), 4.17 (s, 3 H, N₂-CH₃), 2.35 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 165.9 (o), 132.9 (o), 132.3 (+), 132.1 (o), 131.5 (+), 128.6 (+), 127.8 (+), 124.6 (o), 38.2 (+), 36.1 (+), 9.8 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 116.7 (q, J = 11.9 Hz).

HRMS (ESI): m/z [M]⁺ calcd for C₁₃H₁₆N₃OSe⁺: 310.0453; found: 310.0458.

1,2-Dimethyl-4-(2-methylbenzamido)-3-(methylselanyl)-1H-pyrazolium Iodide (21b)

Yield: 44 mg (97%); white solid; mp 177.2 °C.

IR (ATR): 3140, 3037, 2963, 2918, 1669, 1599, 1570, 1493, 1479, 1428, 1410, 1378, 1356, 1293, 1268, 1215, 1170, 1160, 1137, 1098, 1074, 1047, 991, 9783, 925, 913, 878, 8493, 785, 745, 716, 696, 658, 628, 609, 562, 552, 513, 507, 459 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.38 (s, 1 H, NH), 8.90 (s, 1 H, 5-H_pyrazole), 7.54–7.49 (m, 1 H, C₆H₄), 7.46–7.42 (m, 1 H, C₆H₄), 7.36–7.32 (m, 2 H, C₆H₄), 4.22 (s, 3 H, N₁-CH₃), 4.16 (s, 3 H, N₂-CH₃), 2.42 (s, 3 H, CH₃), 2.35 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 168.3 (o), 135.7 (o), 135.3 (o), 130.9 (+, o), 130.7 (+), 130.3 (+), 127.5 (+), 125.7 (+), 124.8 (o), 38.1 (+), 36.0 (+), 19.5 (+), 10.0 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 111.3 (q, J = 11.9 Hz).

HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₈N₃OSe⁺: 324.0610; found: 324.0614.

4-(Cyclopropanecarboxamido)-1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium Iodide (21c)

Yield: 286 mg (97%); white solid; mp 192.2 °C.

IR (ATR): 3216, 3144, 3122, 3083, 3034, 3001, 2917, 2851, 2352, 1658, 1571, 1520, 1497, 1483, 1447, 1411, 1366, 1265, 1224, 1200, 1179, 1165, 1117, 1106, 1083, 1057, 1026, 954, 931, 899, 879, 839, 821, 706, 671, 638, 588, 536 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.19 (s, 1 H, NH), 8.79 (s, 1 H, 5-H_pyrazole), 4.16 (s, 3 H, N₁-CH₃), 4.11 (s, 3 H, N₂-CH₃), 2.33 (t, J = 5.6 Hz, 3 H, Se-CH₃), 2.08–2.03 (m, 1 H, CH), 0.088–0.79 (m, 4 H, CH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 172.4 (o); 129.6 (+), 128.3 (o), 125.4 (o), 38.0 (+), 35.8 (+), 13.4 (+), 10.0 (+), 7.8 (–).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 103.6.

HRMS (ESI): m/z [M]⁺ calcd for C₁₀H₁₆N₃OSe⁺: 274.0453; found: 274.0460.

1,2-Dimethyl-3-(methylselanyl)-4-propionamido-1H-pyrazolium Iodide (21d)

Yield: 177 mg (98%); white solid; mp 203.0 °C.

IR (ATR): 3202, 3170, 3146, 30745, 3032, 3005, 2969, 2935, 2919, 2876, 1738, 1673, 1572, 1520, 1504, 1487, 1458, 1404, 1361, 1263, 1222, 1191, 118, 1089, 1074, 1054, 1026, 929, 916, 872, 849, 804, 719, 673, 650, 613, 591, 567, 535 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.86 (s, 1 H, NH), 8.81 (s, 1 H, 5-H_pyrazole), 4.17 (s, 3 H, N₁-CH₃), 4.11 (s, 3 H, N₂-CH₃), 2.43 (q, 2 H, J = 7.5 Hz, CH₂), 2.32 (t, ¹ J _H–Se = 11.6 Hz, 3 H, Se-CH₃), 10.8 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 172.6 (o), 129.6 (+), 128.5 (o), 125.3 (o), 38.0 (+), 35.8 (+), 28.3 (–), 9.9 (+), 9.5 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 103.9.

HRMS (ESI): m/z [M]⁺ calcd for C₁₇H₁₆N₃O⁺: 278.1288; found: 278.1298.

4-(3,3-Diethylureido)-1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium Iodide (21e)

Yield: 50 mg (>99%); white solid; mp 154.4 °C.

IR (ATR): 3318, 3119, 2976, 2931, 2872, 1638, 1589, 1526, 1479, 1446, 1416, 1402, 1376, 1362, 1331, 1310, 1262, 1215, 1158, 1093, 1078, 1064, 1030, 970, 927, 869, 835, 787, 776, 752, 650, 618, 554, 830, 493, 451, 408 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.53 (s, 1 H, 5-H_pyrazole), 8.08 (s, 1 H, NH), 4.16 (s, 3 H, N₁-CH₃), 4.11 (s, 3 H, N₂-CH₃), 3.33 (q, J = 7.0 Hz, 4 H, CH₂), 2.29 (s, 3 H, Se-CH₃), 1.11 (t, J = 7.0 Hz, 6 H, CH₃) ppm.

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 154.3 (o), 131.8 (o), 131.0 (+), 126.5 (o), 40.8 (–), 37.9 (+), 35.9 (+), 13.7 (+), 9.4 (+) ppm.

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 109.6 (q, J = 12.0 Hz).

HRMS (ESI): m/z [M]⁺ calcd for C₁₁H₂₁N₄OSe⁺: 305.0875; found: 305.0889.

4-Benzamido-2-methyl-3-(methylselanyl)-1-phenyl-1H-pyrazolium Iodide (21h)

Yield: 336 mg (99%); yellow solid; mp 157.6 °C.

IR (ATR): 3393, 2998, 2924, 2854, 2357, 2319, 2213, 2198, 2168, 2148, 2097, 1976, 1661, 1574, 1524, 1490, 1446, 1417, 1390, 1267, 1177, 1122, 1096, 1074, 1025, 1005, 924, 903, 817, 797, 767, 707, 691, 635, 582, 546, 536, 477, 413 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 10.54 (s, 1 H, NH), 9.05 (s, 1 H, 5-H_pyrazole), 8.02–7.99 (m, 2 H, C₆H₅), 7.85–7.82 (m, 2 H, N₁-C₆H₅), 7.80–7.74 (m, 3 H, N₁-C₆H₅), 7.69–7.65 (m, 1 H, C₆H₅), 7.62–7.57 (m, 2 H, C₆H₅), 3.95 (s, 3 H, N₂-CH₃), 2.49 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 166.1 (o), 135.7 (o), 133.3 (o), 132.9 (o), 132.4 (+), 132.3 (+), 132.2 (+), 130.2 (+), 128.7 (+), 127.9 (+), 127.6 (+), 125.4 (o), 37.7 (+), 9.6 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 137.6.

HRMS (ESI): m/z [M]⁺ calcd for C₁₈H₁₈N₃OSe⁺: 372.0610; found: 372.0619.

1,2-Dimethyl-4-(N-methylbenzamido)-3-(methylselanyl)-1H-pyrazolium Iodide (21i)

Yield: 42 mg (97%); yellow solid; mp 161.1 °C.

IR (ATR): 3421, 2999, 2928, 2043, 2010, 17443, 1633, 1600, 1564, 1512, 1493, 1445, 1428, 1404, 1343, 1278, 1241, 1178, 1128, 1076, 1062, 1025, 925, 871, 838, 791, 767, 751, 718, 699, 668, 653, 627, 601, 565, 496, 439 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.78 (s, 1 H, 5-H_pyrazole), 7.48–7.32 (m, 5 H, C₆H₅), 4.16 (s, 3 H), 4.05 (s, 3 H), 3.27 (s, 3 H), 2.12 (s, 3 H).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 170.4 (o), 136.3 (o), 135.0 (o), 130.9 (+), 128.7 (+), 127.7 (+), 126.1 (+), 40.5 (+), 39.0 (+), 36.8 (+), 10.0 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 116.6.

HRMS (ESI): m/z [M]⁺ calcd for C₁₄H₁₈N₃OSe⁺: 324.0610; found: 324.0614.

NMR assignment not possible due to broadened signals in the ¹H NMR spectra.

Preparation of the Selenoether Betaines 22a–e,h,i; General Procedure

The corresponding salt 21a–e,h,i was dissolved in distilled water and added dropwise on an ion-exchange-column charged with Amberlite IR 400 in its hydroxide forms. The product was collected, the water was distilled off in vacuo, and the resulting solid was dried in vacuo.

Benzoyl(1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium-4-yl)amide (22a)

Yield: 217 mg (99%); yellow solid; mp 166.4 °C.

IR (ATR): 3153, 3062, 3000, 2932, 1660, 1601, 1582, 1533, 1491, 1435, 1409, 1373, 1284, 1209, 1186, 1165, 1150, 1122, 1075, 1062, 1018, 988, 925, 617, 891, 843, 822, 803, 722, 708, 697, 677, 627, 589, 572, 545, 526, 475, 447, 433 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.93 (s, 1 H, 5-H_pyrazole), 8.08–8.06 (m, 2 H, C₆H₅), 7.44–7.39 (m, 3 H, C₆H₅), 4.14 (s, 3 H, N₁-CH₃), 4.08 (s, 3 H, N₂-CH₃), 2.50 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 165.9 (o), 138.0 (o), 132.9 (o), 130.3 (+), 130.2 (+), 129.9 (+), 127.9 (+), 127.7 (+), 37.4 (+), 35.3 (+), 8.5 (+).

⁷⁷Se NMR (DMSO-d ₆, 114 MHz): δ = 118.6.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₃H₁₅N₃OSe⁺: 310.0453; found: 310.0460.

(1,2-Dimethyl-3-(methylselanyl)-1H-pyrazolium-4-yl)(2-methylbenzoyl)amide (22b)

Yield: 38 mg (99%); white solid; mp 161.0 °C.

IR (ATR): 3349, 3143, 3010, 2922, 1652, 1599, 1574, 1528, 1510, 1439, 1404, 1370, 1271, 1191, 1166, 1133, 1103, 1038, 918, 894, 878, 845, 818, 792, 740, 690, 678, 649, 625, 568, 541, 530, 520, 471, 456, 419 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.90 (s, 1 H, 5-H_pyrazole), 7.53–7.50 (m, 2 H, C₆H₄), 7.39–7.34 (m, 1 H, C₆H₄), 7.30–7.25 (m, 1 H, C₆H₄), 4.19 (s, 3 H, N₁-CH₃), 4.13 (s, 3 H, N₂-CH₃), 2.43 (s, 3 H, CH₃), 2.38 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 169.0 (o), 137.0 (o), 135.6 (o), 130.6 (+), 130.5 (+), 130.4 (o), 129.5 (o), 127.7 (+, o), 125.4 (+), 37.9 (+), 35.7 (+), 19.8 (+), 9.6 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 110.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₄H₁₇N₃OSe⁺: 324.0610; found: 324.0615.

Cyclopropanecarbonyl(1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium-4-yl)amide (22c)

Yield: 31 mg (99%); white solid; mp 115.2 °C.

IR (ATR): 3343, 3227, 3189, 30973, 3009, 2920, 21773, 2162, 1670, 1633, 1580, 1543, 1494, 1447, 1413, 1366, 1279, 1227, 1193, 1168, 1110, 1096, 1062, 1023, 955, 923, 910, 887, 870, 835, 738, 681, 625, 293, 253, 534 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.77 (s, 1 H, 5-H_pyrazole), 4.13 (s, 3 H, N₁-CH₃), 4.09 (s, 3 H, N₂-CH₃), 2.35 (s, 3 H, Se-CH₃), 1.99–1.91 (m, 1 H, CH), 0.79–0.74 (m, 4 H, CH₂).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 172.3 (o), 129.5 (+), 128.1 (o), 37.8 (+), 35.6 (+), 14.1 (+), 9.6 (+), 7.4 (–).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 102.9.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₀H₁₅N₃OSe⁺: 274.0453; found: 274.0462.

(1,2-Dimethyl-3-(methylselanyl)-1H-pyrazolium-4-yl)(propionyl)amide (22d)

Yield: 33 mg (99%); white solid; mp 143.1 °C.

IR (ATR): 3138, 2974, 2940, 1673, 1611, 1576, 1527, 1492, 1450, 1408, 1365, 1268, 1223, 1194, 1170, 1127, 1073 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.79 (s, 1 H, 5-H_pyrazole), 4.15 (s, 3 H, N₁-CH₃), 4.09 (s, 3 H, N₂-CH₃), 2.41–2.31 (m, 5 H, CH₂, Se-CH₃), 1.06 (t, J = 7.5 Hz, 3 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 173.2 (o), 129.5 (+), 128.4 (o), 127.2 (o), 37.9 (+), 35.7 (+), 28.9 (–), 9.8 (+), 9.7 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 106.3.

HRMS (ESI): m/z [M + H]⁺ calcd for C₉H₁₅N₃OSe⁺: 262.0453; found: 262.0451.

(Diethylcarbamoyl)(1,2-dimethyl-3-(methylselanyl)-1H-pyrazolium-4-yl)amide (22e)

Yield: 34 mg (98%); white solid; mp 152.0 °C.

IR (ATR): 3442, 3138, 3079, 2971, 2953, 2670, 1631, 1576, 1532, 1487, 1428, 1390, 1358, 1278, 1219, 1194, 1161, 1085, 1062, 1085, 1062, 1003, 978, 916, 8776, 838, 783, 749, 677, 617, 593, 575, 542, 444 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 8.49 (s, 1 H, 5-H_pyrazole), 4.08 (s, 3 H, N₁-CH₃), 4.04 (s, 3 H, N₂-CH₃), 3.32 (q, J = 7.0 Hz, 4 H, CH₂), 2.36 (s, 3 H, Se-CH₃), 1.06 (t, J = 7.0 Hz, 6 H, CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 158.1 (o), 129.4 (+), 129.3 (o), 129.2 (o), 40.4 (–), 37.4 (+), 35.3 (+), 14.1 (+), 8.3 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 108.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₁H₂₀N₄OSe⁺: 305.0875; found: 305.0872.

Benzoyl(2-methyl-3-(methylselanyl)-1-phenyl-1H-pyrazolium-4-yl)amide (22h)

Yield: 120 mg (99%); yellow solid; mp 133.9 °C.

IR (ATR): 3144, 3057, 2965, 1636, 1592, 1526, 1490, 1448, 1409, 1378, 1282, 1250, 11583, 1130, 1107, 1074, 1026, 1003, 952, 923, 895, 830, 800, 764, 693, 610, 583, 556, 496, 456 cm^–1.

¹H NMR (DMSO-d ₆, 600 MHz): δ = 9.04 (s, 1 H, 5-H_pyrazole), 8.09–7.99 (m, 1 H, C₆H₅), 7.83–7.78 (m, 2 H, N₁-C₆H₅), 7.78–7.70 (m, 3 H, N₁-C₆H₅), 7.60–7.55 (m, 1 H, C₆H₅), 7.55–7.47 (m, 2 H, C₆H₅), 3.92 (s, 3 H, N₂-CH₃), 2.56 (s, 3 H, Se-CH₃).

¹³C NMR (DMSO-d ₆, 150 MHz): δ = 166.8 (o), 135.0 (o), 133.5 (o), 132.0 (+), 131.4 (+), 131.3 (+), 130.2 (+), 129.1 (o), 128.3 (+), 127.5 (+), 37.5 (+), 9.1 (+).

⁷⁷Se NMR (DMSO-d ₆, 76 MHz): δ = 138.4.

HRMS (ESI): m/z [M + H]⁺ calcd for C₁₈H₁₇N₃OSe⁺: 372.0610; found: 372.0616.

Conflict of Interest

The authors declare no conflict of interest.

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Corresponding Author

Publication History

Received: 04 February 2022

Accepted after revision: 17 February 2022

Article published online:
20 April 2022

© 2022. Thieme. All rights reserved

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

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• 54b Frosch J, Koneczny M, Bannenberg T, Tamm M. Chem. Eur. J. 2021; 4349
  CrossrefPubMed
• 54c Grineva AA, Valyaev DA, César V, Filippov OA, Khrustalev VN, Nefedov SE, Lugan N. Angew. Chem. Int. Ed. 2018; 57: 7986 ; Angew. Chem. 2018, 130, 8118
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