Synthesis of Diverse N-Trifluoromethyl Pyrazoles by Trapping of Transiently-Generated Trifluoromethylhydrazine

Bao Li^†, Fenglei Xie^†, Rui Zhang^†, Yaoyi Wang^†, Vijaya B. Gondi^‡, and Christopher R. H. Hale^‡*

^†WuXi AppTec Research Chemistry Services, 168 NanHai Road, 10th Avenue, TEDA, Tianjin, 300457, China

^‡ Karuna Therapeutics – A Bristol Myers Squibb Company, Chemical Development, 99 High Street, Floor 26, Boston, Massachusetts 02110, United States

*Email: khale@karunatx.com

ABSTRACT

A one-pot synthesis of functionalized N-trifluoromethyl pyrazoles from readily available di-Boc trifluoromethylhydrazine and dialdehydes, diketones, carbonylnitriles, and keto-esters/amides/acids is described. ¹⁹F NMR studies were used to characterize the stability of trifluoromethylhydrazine HCl salt in solution and in solid form and identified a short solution-state half-life of ~6 hours. Optimization of cyclization conditions identified DCM, combined with a strong acid, as key to suppress the undesired des-CF₃ side-products which formed as a result of the instability of trifluoromethylhydrazine and related intermediates. Despite the short-lived nature of these transient intermediates, their reactivity could be utilized to directly deliver a diverse array of pharmaceutically-relevant N-trifluoromethyl pyrazoles in synthetically useful yields.

INTRODUCTION

The trifluoromethyl moiety is ubiquitous within the field of medicinal chemistry due to its well-documented properties of improving metabolic stability, cell permeability, and potency.[1] Fluorine, from a bioisosteric perspective, has found widespread use as a replacement for hydrogen atoms, methyl groups, and carbonyls as well as for amides, ureas, and nitriles.^1a,[2]^,[3] However, significant challenges remain in the preparation of heteroatom-linked trifluoromethyl moieties. Methods for the preparation of the N­-CF₃ functionality have been reviewed and generally include tactics such as fluorinative desulfurization, use of electrophilic CF₃ sources such as the Togni reagent or functionalized phthalimides, generation of thiocarbamoyl fluorides, carbon disulfide/DAST, use of CF₃-derivatized hydroxylamines, or nitrilium generation via PhICF₃Cl.[4]^,[5]  More specifically, there is an interest in the N-CF₃ pyrazole moiety for pharmaceutical applications as shown by the representative examples in Figure 1.

Figure 1. Representative examples of pharmaceutically-relevant N-CF₃ pyrazoles

Unfortunately, existing methods for the preparation of the N-CF₃ pyrazole, despite its known utility in medicinal chemistry, are much more limited and only include either step-wise CF₃ installation using environmentally detrimental CF₂Br₂ (a class 1 ozone-depleting substance)[6] followed by bromine displacement with a fluoride source (either from silver reagents[7] such as AgBF₄, or Me₄NF under harsh temperatures[8]), or the Togni reagent^5a, as summarized in Figure 2. However, such conditions are difficult to implement from an environmental, cost, waste, and safety perspective required for clinical and commercial supply of these compounds. Therefore, improved synthetic methods to prepare N-CF₃ pyrazoles are highly desirable. In this article, we describe our efforts to develop a scalable and process-friendly approach using dicarbonyl compounds and trifluoromethylhydrazine as the building blocks (Figure 2).

Figure 2. Previous and current approaches to the N-CF₃ pyrazole motif

RESULTS AND DISCUSSION

During our initial explorations, we identified the 2021 publication by Crousse[9] who reported the preparation of N-CF₃ di-Boc hydrazine 3 via reaction of DBAD (1) with CF₃-radical precursor sodium triflinate (2, Langlois reagent[10]) under oxidative conditions (TBHP) and two examples of in-situ deprotection to generate transient trifluoromethylhydrazine 6 (as HCl salt) with subsequent cyclization with 1,3-dicarbonyl compounds 4 and 5 to produce pyrazoles 7 and 8 (44-46% yield, Scheme 1). Seeking to build upon that work, our team sought to 1) improve upon the preparation of N-CF₃ di-Boc hydrazine 3, 2) understand the stability of trifluoromethylhydrazine 6 as a solid and in solution, 3) optimize the conditions and expand upon the scope of the reaction of trifluoromethylhydrazine (6) with 1,3-dicarbonyl compounds and related substrates, and 4) explore the synthesis and utility of related congeners such as difluoromethylhydrazine.

Scheme 1. Crousse Precedent for N-CF₃ Pyrazole Synthesis⁹ 

At the onset of our studies, we sought to replicate the conditions of Crousse for the preparation of 3. In our hands, we could not achieve the same yield or product ratio as described by Crousse⁹ under identical conditions, instead, obtaining 19% yield (versus 57%) and a 4:1 ratio of 3:3b (versus 98:2, entry 1, Table 1). Based on this data, we set out to optimize the conditions for better yield and selectivity. A summary of our optimization efforts is described in Table 1. Lowering the temperature slightly improved both selectivity and yield (entry 2). Varying the solvent to acetonitrile provided a marked improvement in product distribution (entry 3) but no improvement in yield. Alternatively, we found that reversing the order of addition by adding TBHP last gave significantly higher yields (50-57%) and improved product ratio (>100:1 3:3b, entries 5-7) with DMSO as solvent, in contrast to the report of Crousse. We observed a relatively modest effect of temperature on the reaction yield, with the highest yields obtained when the temperature was maintained below 10 °C (entry 5). Small quantities of side-product di-Boc hydrazine (3c) could be detected in some cases (<2% by GC analysis). The preferred conditions (entry 5) were successfully scaled to 50 g of DBAD to prepare 40.6 g of the key compound 3 in a single batch (62% yield).

Table 1. Optimization of Trifluoromethylation of DBAD

#	Addition Order	Solvent	Temp (℃)	3:3b ratio (by 19F NMR)	Yield (%)
1a	CF3SO2Na last	DMSO	RT	4:1	19
2		DMSO	10-15	9:1	38
3		MeCN	10-15	80:1	25
4		DCM/ H2O (4:1)	10-15	Low conversion
5	TBHP last	DMSO	5-10	>100:1	57
6		DMSO	10-15	>100:1	55
7		DMSO	15-25	>100:1	50
8		MeCN	10-15	Complex 19F NMR

Notes: Reactions conducted on 2.0 mmol scale using 1.5 eq of CF₃SO₂Na and 1.5 eq TBHP. a) conditions from reference 9.

Next, prior to studying the cyclization reaction, 6•HCl salt was prepared⁹ as a white solid by treatment of 3 with HCl/dioxane followed by concentration in order to assess any potential thermal hazards and evaluate the chemical stability of trifluoromethylhydrazine. The differential scanning calorimetry (DSC) profile of 6•HCl showed no exothermic event and a mild endotherm around 89 ℃, similar to the known melting point for hydrazine hydrochloride. The stability characteristics of trifluoromethylhydrazine 6 in solution and the solid state were next evaluated via ¹⁹F NMR using 4-fluorobenzoic acid as a standard. As summarized in Figure 3, trifluoromethylhydrazine HCl salt exhibits generally poor stability in solution (DMSO and MeOH), with a t_1/2 of ~6 hours. Improved stability was observed in the solid state, as expected, but solid trifluoromethylhydrazine HCl was predominantly decomposed after 10 days (5.5% remained by ¹⁹F NMR analysis against an internal standard). The decomposition of trifluoromethylhydrazine probably involves elimination of HF, likely via a bimolecular process based on orbital symmetry rules forbidding the unimolecular HF elimination.[11] In support of this, we observed the major impurity under certain cyclization conditions (vide infra) to be the analogous des-CF₃ pyrazoles, indicating that trifluoromethylhydrazine, its mono-Boc congener, and/or a condensation/cyclization intermediate are unstable and decompose to hydrazine or hydrazine adducts. Similar stability trends are described in the literature for both the related trifluoromethylamine (as the free-base) and trifluoromethanol, both of which decompose below 0 ℃.¹¹ We attempted to prepare the free-base of trifluoromethylhydrazine via hydrogenolysis of the corresponding bis-Cbz-trifluoromethylhydrazine (see the Supporting Information). However, under these conditions, no spectroscopic evidence for the formation of free-base 6 was observed, suggesting that free-base trifluoromethylhydrazine is even less stable than 6•HCl. These results suggest that protonation of 6 is important to prevent rapid decomposition to other hydrazine-like side-products. With this data in-hand, we hoped to be able to leverage the transient kinetic stability of trifluoromethylhydrazine under acidic conditions to expand its utility into more cyclization reactions.

Figure 3. Stability of trifluoromethylhydrazine hydrochloride (6•HCl) as solid and in solution

^aEvaluated using 4-fluorobenzoic acid as an internal standard via ¹⁹F NMR.

We began our cyclization optimization studies using compound 5 as a model substrate with a specific aim of optimizing the selectivity between 8a and undesired 8b.⁹ These studies are summarized in Table 2. As described in entries 1-5, we initially screened several acids at elevated temperature in either dioxane or ethanol. Using acetic acid in dioxane, very poor conversion was observed (entry 1). Switching to stronger acids (TFA, HCl, or TsOH) at elevated temperature (entries 2-5) resulted in the desired product 8a as major, although with significant quantities of undesired des-CF₃ 8b (8a:8b selectivity ranging from 63:37 to 94:6). Decreasing the temperature (entry 6) proved critical in completely suppressing the undesired 8b. For ease of handling, aqueous work-up, and isolation considerations, we moved to TsOH/DCM at mild temperature for further studies (entries 7-11), which generally provided excellent selectivity for the desired product 8a and no detectable 8b. While the equivalents of TsOH and 5 could be reduced to as low as 2 eq and 0.6 eq, respectively, with no impact to the 8a:8b selectivity (entries 9-10), in some cases we observed evidence of incomplete Boc deprotection (entry 10), leading us to select 5 eq of acid as the preferred acid quantity.  For yield and efficiency considerations, we selected 1.2 eq of the carbonyl partner as the preferred conditions for subsequent substrate scope investigations (entry 11, highlighted). Under these optimized conditions, 8a could be obtained in 75% isolated yield (Scheme 2). Finally, we re-investigated the use of TFA but with the preferred solvent (DCM) and temperature (20-40 °C) and observed that the formation of impurity 8b was also effectively suppressed (entry 12).

Table 2. Optimization of Cyclization Conditions

#	Acid/ Solv.	Acid eq.	Eq. 5	Temp (°C) / time	8a:8ba
1	AcOH/ Diox.	10	1.5	80/12h	N.D.
2	TFA/ Diox.	10	1.5	80/12h	85:15
3	HCl/ EtOH	10	1.5	50/3h	94:6
4	TsOH/ EtOH	5	1.5	50/12h	63:37
5	TsOH/ EtOH	5	1.5	50/3h	91:9
6	HCl/ EtOH	10	1.5	20/12h	100:0
7	TsOH/ DCM	5	1.5	20-40/12h	100:0
8	TsOH/ DCM	5	1.0	20-40/12h	100:0
9	TsOH/ DCM	2	1.0	20-40/12h	100:0
10	TsOH/ DCM	2	0.6	20-40/12h	100:0b
11	TsOH/DCM	5	1.2	20-40/12h	100:0
12	TFA/ DCM	10	1.5	20-40/12h	100:0

Notes: All experiments conducted on 2 mmol of 3. ^aAs determined by LCMS area%.  ^bIncomplete Boc deprotection was observed by ¹H NMR

With our preferred reaction conditions now defined (Table 2, entry 11: 5 eq TsOH, 1.2 eq of cyclization partner, DCM, 20-40 °C), we proceeded to explore the substrate scope of the one-pot Boc-deprotection/cyclization sequence. Gratifyingly, despite the short half-life of trifluoromethylhydrazine, we found this methodology to be readily applicable to a variety of substrate classes and obtained the desired pyrazole products in synthetically-useful yields, as shown in Scheme 2. 1,3-Diketones are generally successful substrates in this transformation, with products 7a-10 obtained with a variety of substitution patterns (up to fully-substituted pyrazole for 9) and electronics (alkyl, aromatic, electron-withdrawing) tolerated in 47-75% yield. Of note is that methyl acetopyruvate was converted to a separable mixture of two regioisomers of 10, both of which contain a key functional handle of an ester for additional manipulations and amide bond formation. In the case of non-symmetrical products (i.e. 7a), we found that the terminal nitrogen from trifluoromethylhydrazine condenses onto the more electron-deficient carbonyl moiety, with the N-CF₃ substitution residing proximal to the arene. 1,3-Dialdehydes are even better substrates (11-15, Scheme 2), likely because of the more rapid trapping of unstable NH-CF₃ intermediates. In these cases, yields of 68-82% were achieved for products 11-15. Aryl and heteroaryl-substituted dialdehydes were well tolerated.

To further expand the scope and to provide additional functional handles for downstream manipulation, cyclizations were attempted using 1,3-ketonitriles and 1,3-cyanoaldehydes to produce amino-substituted N-CF₃-pyrazoles 16-21 in 26-63% yield (Scheme 2). In these cases, the terminal nitrogen likely condenses with the carbonyl first, followed by trapping of the NH-CF₃ with the adjacent nitrile to form the amine. The regiochemistry of the products 16-20 derived from ketonitrile substrates was confirmed by ¹H-¹⁹F HOESY experiments which clearly identified the strong through-space interaction observed between the NH₂ and CF₃ moieties. The lower yield in some cases (e.g. 18, 19) of the nitrile-containing substrates could be a result of competing factors such as t-butyl-cation-induced Ritter reaction, t-butylation of the product amines, slower kinetics of cyclization onto the nitrile moiety leading to des-CF₃ impurities, or higher aqueous solubility of the primary amine products. In some cases, tert-butylated impurities could be reduced by switching the solvent from DCM to EtOH (see the Supporting Information for more details). For instance, during studies to produce product 18, the t-butylated analog 18b was isolated in 15% yield and fully characterized (Figure 4). Similarly, the t-butylated β-ketoamide 19a was isolated in 20% yield (Figure 4) during the reaction to produce the 4-bromophenyl product 19.

Finally, several β-ketoesters, β-ketoacids, and β-ketoamides were subjected to trifluoromethylhydrazine cyclization to generate N-CF₃ hydroxypyrazoles or pyrazolones (Scheme 2, 22–25, 36-55% yield). Both ethyl and phenyl esters were successful substrates, providing desired pyrazoles in similar yields (22-24). We also discovered that keto-acids and keto-amides were successful substrates in generating the desired hydroxy-pyrazoles or pyrazolones (23 and 25) which could provide an advantage when a particular ester is difficult to prepare, due to, for example, steric hinderance or other route-of-synthesis considerations.

Scheme 2. Scope of N-trifluoromethyl Pyrazole Cyclization

Notes: Performed on 1.67 mmol scale of 3 unless otherwise noted in the SI. ^aCombined yield of ~1:1 mixture of the two separable regioisomers; ^bR = H (18, 13% yield), R = tBu (18b, 15% yield); ^cStarting from the corresponding keto-phenyl ester; ^dStarting from the corresponding keto-ethyl ester; ^eStarting from the corresponding keto-acid; ^fStarting from the corresponding keto-amide

Figure 4. Isolated impurities from keto-nitrile substrates

A number of unsuccessful substrates warrant discussion since they provide insight on the stability, reactivity, and mechanism of trifluoromethylhydrazine-containing intermediates and transformations. For example, as summarized in Scheme 3, we attempted to prepare azaindazole 29 via condensation of trifluoromethylhydrazine with 2-fluoronicotinaldehyde 26. After 2 hours of reaction time, aldehyde condensation intermediates 27 and 28 were detected in 40% and 37% a/a by LCMS. However, upon extended reaction time, none of the desired N-CF₃-azaindazole 29 could be detected, and a number of unidentified side-products were observed by LCMS. In attempts to recover the azaindazole formation, we added base (DIPEA) and increased the temperature to favor the SNAr, but these efforts did not result in the detection of 29. The NH-CF₃ (e.g. 28) appears to not be nucleophilic enough under these conditions to participate in the SNAr reaction.

Scheme 3. Unsuccessful Generation of N-CF₃-azaindazole 29

Similarly, we attempted to prepare the hydroxy N-CF₃-pyrazole 33 via reaction of trifluoromethylhydrazine with β-ketoester 30 (Scheme 4). As with the results in Scheme 3, we observed that the NH-CF₃ is not nucleophilic enough under these conditions to react with the methyl ester in this specific example, and instead the NH-CF₃ completely hydrolyzes and cyclizes to form the des-CF₃ hydroxypyrazole 31 or alternatively condenses to form dimeric compound 32, both of which were detected by LCMS. These studies provide further evidence that hydrazine is a predominant degradant of trifluoromethylhydrazine.

Scheme 4. Unsuccessful Generation of N-CF₃-hydroxypyrazole 33

Our mechanistic hypothesis for a prototypical cyclization is summarized in Scheme 5. Based on the presence of significant levels of intermediates 27 and 28 (Scheme 3), we postulate that these transformations may undergo, to some extent, step-wise and sequential Boc-deprotections/condensations, although the formation of trifluoromethylhydrazine directly prior to any condensation event seems equally plausible. We suspect that NBoc-CF₃ intermediates (e.g. 27, Scheme 3) are likely stable compounds, but the free NH-CF₃ (e.g. 28, Scheme 3) will be highly prone to beta-elimination of HF initiating hydrolytic cleavage of CF₃ via diflouroimine and/or fluoroformate-like reactive intermediates.^3a,[12] Upon Boc deprotection of the NBoc-CF₃, it appears critical to quickly trap the NH-CF₃ with a reactive electrophilic moiety (ketone, aldehyde, nitrile, or carboxylic moiety) at relatively mild temperature (<50 °C).

Scheme 5. Proposed Mechanisms for the Formation of N-CF₃ and des-CF₃ Pyrazoles

In efforts to expand the scope of this methodology, we sought to apply the same strategies to the analogous difluoromethyl pyrazoles, which are also of pharmaceutical interest.[13] Initially, we attempted to use commercially available zinc bis-difluoromethanesulfinate under conditions described by Baran[14] to yield CHF₂ radical and add across DBAD (1, Scheme 6). However, we were surprised to find that these conditions yielded almost exclusively the undesired difluoromethyl sulfonamide product 34, with only traces of 35 detectible by mass spectrometry (Scheme 6, top). The analogous sodium difluoromethanesulfinate[15] was also unsuccessful in providing the desired product 35. Turning to nucleophilic CHF₂ sources, we next attempted to utilize the difluoro analog of the Ruppert-Prakash reagent[16], since TMSCHF₂ is also a known nucleophilic CHF₂ anion source under more forcing conditions than those needed with TMSCF₃.[17],[18] Indeed, these conditions did yield some small quantity of desired 35, albeit in low yield (11%, Scheme 6, Conditions B). Finally, we turned to generation of the CF₂ carbene from TMSCF₂Br and KOH, which successfully underwent N-H insertion with di-Boc hydrazine 3c to generate 35 in 49% isolated yield.[19] The related bis-Cbz product 37 was also prepared in the same manner.

Scheme 6. Preparation of bis-Boc and bis-Cbz Difluoromethylhydrazines 35 and 37

Next, as shown in Scheme 7, we attempted to generate difluoromethylhydrazine 38 either as the HCl, TsOH, or TFA salt under acid-mediated Boc deprotection conditions or as free-base via palladium-catalyzed hydrogenolysis of bis-Cbz precursor 37. However, we could not detect any peak in ¹H or ¹⁹F NMR attributable to the desired difluoromethylhydrazine 38 or salt. Instead, mixtures of several high or low field ¹⁹F NMR signals were observed. According to the report of Schiesser^3a whose team conducted detailed stability studies on dialkyl-trifluoromethylamines (e.g. R₂NCF₃), the N-CF₃ moieties are only hydrolytically stable when the R groups are sufficiently electron deficient as in the case of pyrazole rings. Considering this, we surmised that the lack of the third fluorine atom on the CHF₂ carbon may result in the N-CHF₂ being more electron-rich, thereby substantially decreasing its stability. Alternatively, difluoromethylhydrazine is likely a stronger base than its trifluoromethyl congener, which could result in faster bimolecular elimination of HF.

Scheme 7. Attempted Generation of Difluoromethylhydrazine 38

Despite this setback, we hoped that if difluoromethylhydrazine 38 could be generated in-situ in the presence of a reactive trapping agent, such as dialdehyde 39 (Scheme 8), that we might be able to realize the successful preparation of N-difluoromethyl pyrazoles (e.g. 40, Scheme 8). Unfortunately, when 35 or 37 was subjected to acid-mediated or hydrogenolytic cleavage of the Boc or Cbz moieties in the presence of dialdehyde 39, the desired difluoromethyl pyrazole 40 was still not detected, indicating the lifetime of difluoromethylhydrazine 38 (or its mono-Boc or mono-Cbz analog) is exceptionally short under ambient conditions as either the salt or the free-base.

Scheme 8. Attempted Preparation of Difluoromethyl Pyrazole 40 by Trapping of Difluoromethylhydrazine

CONCLUSION

In conclusion, we have developed an effective method to prepare N-trifluoromethyl substituted pyrazoles via condensation of transiently-generated trifluoromethylhydrazine to produce a variety of substitution patterns and functionalizations on the pyrazole ring. Optimization of the cyclization conditions via careful selection of the acid, solvent, and temperature was critical in reducing the formation of des-CF₃ pyrazole impurities. Stability studies also informed on the lifetime of trifluoromethylhydrazine HCl salt as solid and in solution. Efforts to expand this methodology to the analogous difluoromethyl pyrazoles were unsuccessful due to possible stability differences between trifluoro- and difluoro-methylhydrazine. Of particular value is that this method of directly generating the N-CF₃ pyrazole avoids many of the previously-described synthetic challenges including the use of HF, stoichiometric silver reagents, and ozone-depleting substances, and instead relies upon more widely available, cost-effective, and pharmaceutically-acceptable materials.

EXPERIMENTAL SECTION

General Information. All reactions were carried out under a nitrogen atmosphere unless otherwise noted. All solvents used were dried prior to use via passage through an activated alumina column or purchased as anhydrous grade. Yields refer to chromatographically and spectroscopically homogeneous material (¹H NMR), unless otherwise stated. Reactions were monitored by thin-layer chromatography (TLC) carried out on silica gel plates (Liangcheng, particle size 5-20 μm, 200 – 400 mesh) and were visualized using UV light and an ethanolic solution of phosphomolybdic acid or an aqueous solution of potassium permanganate or LCMS (instrument details are shown below). NMR spectra were recorded on a Bruker Avance 400 (400 MHz for ¹H, 100 MHz for ¹³C, 376 MHz for ¹⁹F) spectrometer equipped with a BBFO-SP/Z116098 probe (PA BBO 400S1 BBF-H-D-05-Z SP) and calibrated using residual undeuterated solvent for ¹H NMR [¹H = 7.27 (CHCl₃) and 2.50 (D₅H-DMSO) ppm] and ¹³C deuterated solvent for ¹³C NMR [¹³C = 77.16 (CDCl₃), 39.52 (D₆-DMSO) and 49.00 (CD₃OD) ppm] as an internal reference at 298 K or 353K. The following abbreviations were used to designate the multiplicities: s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad, ap = apparent. The identification of structures was achieved using a combination of ¹H NMR, ¹³C NMR, DEPT, COSY, HMBC, HMQC, HOESY, and NOESY experiments. Coupling constants (J) are reported in Hertz (Hz). ATR-Infrared (IR) spectra were recorded on a Thermo-NICOLET iS10FT-IR spectrometer. Mass spectrometric data were recorded on an Agilent 1260 LC/MS spectrometer using ESI (electrospray ionization), a Shimadzu LC-20AD+2020MS using ESI or a Waters ACQUITY XEVO G2-XS QTOF using ESI.  Preparative HPLC separations were performed using a Gilson 281 Semi-preparative HPLC system equipped with a Phenomenex Luna C18 100*40mm*3 μm or Waters Xbridge Prep OBD C18 150*40mm*10μm column and monitored using a Gilson 1741 photodiode array detector. All reactions requiring heating were heated using an IKA RCT Basic stir plate equipped with metallic heating blocks. Caution! Hydrazine-containing compounds (e.g. 6) have the potential to be mutagenic, carcinogenic, and flammable/explosive. Care should be taken when handling these materials.

Di-tert-butyl 1-(trifluoromethyl)hydrazine-1,2-dicarboxylate (3): To a solution of 1 (50 g, 217.1 mmol, 1 eq) in DMSO (1 L) was added a solution of CF₃SO₂Na (50.8 g, 325.7 mmol, 1.5 eq) in H₂O (250 mL). The resulting mixture was cooled to 5 °C with an ice bath. Then a solution of TBHP (29.4 g, 325.7 mmol, 31.2 mL, 70% wt, 1.5 eq) was added over a period of 2.5 hours (exothermic process: the TBHP solution was added very slowly to keep the temperature between 5~10 °C). The mixture was stirred at 5~10 °C for 4 hours. TLC (Petroleum ether/ EtOAc = 4:1, R_f = 0.75, stained with PMA) indicated 1 was consumed completely and one major spot (more polar) formed. The reaction mixture was quenched with water (2 L) and extracted with ethyl acetate (3 × 1 L). The combined organic layers were washed with brine (3 L), dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, petroleum ether/ ethyl acetate= 1/0 to 2/1) to afford 3 (40.6 g, 135.2 mmol, 62% yield) as a white solid. The analytical data conformed to those reported in the literature⁹. 3: FT-IR (neat) ν_max = 3317, 2988, 2940, 1767, 1726, 1511, 1479, 1372, 1305, 1284, 1149, 1063, 902, 850, 796, 761 cm^-1; LCMS: m/z = 299.23 (M-H⁺); HRMS (ESI) calcd for C₁₁H₁₈F₃N₂O₄^– [M-H⁺] 299.1224, found 299.1247; ¹H NMR: (400 MHz, CDCl₃, 298 K) δ (ppm) = 6.61 – 6.15 (m, 1H), 1.52 (s, 9H), 1.49 (s, 9H); ¹⁹F NMR: (376 MHz, CDCl₃, 298 K) δ (ppm) = -59.14 ­­– -59.39; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 154.3, 150.5, 120.5 (q, J = 263.1 Hz, CF₃), 85.0, 82.6, 28.1, 27.9.

Trifluoromethylhydrazine hydrochloride (6•HCl): Prepared using a similar method to that described in reference 9. A solution of 3 (2 g, 6.66 mmol, 1 eq) in HCl/dioxane (4 M, 10 mL, 6.01 eq) was stirred at 20 °C for 1 hr under N₂ atmosphere. TLC indicated 3 was consumed, and one major new spot was detected. The reaction mixture was filtered. Then the filter cake was collected and dried under vacuum to give 6•HCl (0.3 g, 2.2 mmol, 33% yield) as a white solid. 6•HCl: ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 8.57 (br s, 1H), 7.32 (t, ¹J_NH = 51.2 Hz, 3H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -62.7 (s); ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 123.1 (q, J = 260.0 Hz, CF₃); ¹³C{¹H} NMR: (100 MHz, CD₃OD) δ (ppm) = 124.0 (q, J = 260.0 Hz, CF₃).

Dibenzyl 1-(trifluoromethyl)hydrazine-1,2-dicarboxylate (Cbz-3): To a solution of dibenzyl azodicarboxylate (10 g, 33.52 mmol, 1 eq) in DMSO (150 mL) was added a solution of CF₃SO₂Na (7.85 g, 50.29 mmol, 1.5 eq) in H₂O (15 mL). The resulting mixture was cooled to 5 °C with the ice bath. Then a solution of TBHP (6.47 g, 50.29 mmol, 6.89 mL, 70% wt, 1.5 eq) was added over a period of 2.5 hours (exothermic process: the TBHP solution was added very slowly to keep the temperature between 5~10 °C). The mixture was stirred at 10~20 °C for 4 hours. TLC (Petroleum ether/ EtOAc = 4: 1, R_f = 0.75, stained with PMA) indicated dibenzyl azodicarboxylate was consumed completely and one major spot (more polar) formed. The reaction mixture was quenched with water (200 mL) and extracted with ethyl acetate (3 × 100 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, petroleum ether/EtOAc = 1/0 to 2/1) and prep-HPLC (column: Phenomenex Luna C18 100*40mm*5 μm; mobile phase: [A: H₂O with 0.2% formic acid; B: ACN]; gradient: 40%-75% B over 8.0 min) to afford Cbz-3 (1.4 g, 3.8 mmol, 11% yield) as a white solid. Cbz-3: FT-IR (neat) ν_max = 3291, 3036, 2965, 2904, 2764, 2340, 1769, 1720, 1522, 1467, 1396, 1305, 1278, 1247, 1209, 1178, 1070, 1048, 1030, 845, 778, 698, 643, 573, 505 cm^-1; LCMS: m/z = 367.09 (M-H⁺); HRMS (ESI) calcd for C₁₇H₁₄F₃N₂O₄^– [M-H⁺] 367.0911, found 367.0943; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.59 ­– 7.16 (m, 10H), 6.93 – 6.53 (m, 1H), 5.40 – 5.03 (m, 4H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = ­‑59.59 – -59.69; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 155.2, 151.7, 135.1, 134.4, 128.8, 128.7, 128.4, 128.2, 127.9, 120.1 (q, J = 263.1 Hz, CF₃), 69.8, 68.6.

General procedure for the cyclization reaction to prepare N-CF₃ substituted pyrazoles. To a solution of 3 (500 mg, 1.67 mmol, 1.0 eq) and 1,3-dicarbonyl substrate [1,3-diketone/1,3-dialdehyde/1,3-carbonylnitrile/1,3-ketoester/acid/amide (2.00 mmol, 1.2 eq)] in DCM (5 mL) was added TsOH∙H₂O (1.43 g, 8.33 mmol, 5 eq). The mixture was stirred at 20-40 °C for 12 hours. LCMS showed the reaction was completed and the desired product was detected. The reaction was quenched with saturated sodium bicarbonate aqueous solution (5 mL), diluted with water (10 mL), and extracted with DCM (3 × 5 mL) [Note: acetonitrile/brine was used for the extraction of the pyridyl substituted pyrazoles. This series of compounds have high solubility in the aqueous phase.] The combined organic layers were washed with brine (20 mL), dried over Na₂SO₄, and filtered. The filtrate was concentrated under reduced pressure and purified by column chromatography (0%-50% EtOAc:hexanes) to afford the N-CF₃ substituted pyrazoles.

3-Methyl-5-phenyl-1-(trifluoromethyl)-1H-pyrazole (7a): (270 mg, 72% yield) was obtained as yellow oil following the general procedure. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.5, UV 254 nm); FT-IR (neat) ν_max = 3442, 3064, 2933, 1570, 1504, 1446, 1377, 1353, 1300, 1251, 1171, 1095, 961, 816, 781, 721, 698 cm^-1; LCMS: m/z = 227.1 (M+H⁺); HRMS (ESI) calcd for C₁₁H₉F₃N₂H⁺ [M+H⁺] 227.0791, found 227.0807; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.51 – 7.34 (m, 5H), 6.22 (s, 1H), 2.36 (s, 3H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -54.84; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 152.0, 145.6, 129.5, 129.2, 129.1, 128.4, 118.8 (q, J = 263.8 Hz, CF₃), 111.2, 13.6.

3,5-Diphenyl-1-(trifluoromethyl)-1H-pyrazole (8a): (360 mg, 75% yield) was obtained as colorless oil following the general procedure. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.75, UV 254 nm). FT-IR (neat) ν_max = 3439, 3063, 1561, 1489, 1462, 1442, 1406, 1351, 1328, 1299, 1216, 1172, 1100, 959, 950, 770, 693 cm^-1; LCMS: m/z = 289.0 (M+H⁺); HRMS (ESI) calcd for C₁₆H₁₁F₃N₂H⁺ [M+H⁺] 289.0947, found 289.0950; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.95 – 7.83 (m, 2H), 7.56 – 7.36 (m, 8H), 6.72 (s, 1H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -54.87; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 153.8, 146.1, 131.6, 129.7, 129.2, 129.1, 128.9, 128.5, 126.4, 119.0 (q, J = 264.7 Hz, CF₃), 108.3.

3,5-Dimethyl-4-phenyl-1-(trifluoromethyl)-1H-pyrazole (9): (200 mg, 47% yield) was obtained as a colorless oil following a modification of the general procedure using 1.0 eq of diketone. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.7, UV 254 nm). FT-IR (neat) ν_max = 3440, 3062, 2934, 1675, 1611, 1505, 1480, 1381, 1245, 1162, 1077, 1055, 916, 816, 765, 741, 702, 668, 632 cm^-1; LCMS: m/z = 241.0 (M+H⁺); HRMS (ESI) calcd for C₁₂H₁₁F₃N₂H⁺ [M+H⁺] 241.0947, found 241.0950; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.50 – 7.41 (m, 2H), 7.41 – 7.34 (m, 1H), 7.26 – 7.21 (m, 2H), 2.37 (q, ⁵J_H-F = 1.6 Hz, 3H), 2.26 (s, 3H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -57.30; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 150.6, 137.6, 131.8, 129.8, 128.8, 127.6, 123.8, 119.2 (q, J = 262.7 Hz, CF₃), 12.8, 10.6.

Methyl 3-methyl-1-(trifluoromethyl)-1H-pyrazole-5-carboxylate (10a) and methyl 5-methyl-1-(trifluoromethyl)-1H-pyrazole-3-carboxylate (10b): [10a (126 mg, 36% yield), 10b (120 mg, 35% yield)] were obtained following the general procedure, using prep-TLC instead of column chromatography. 10a (white solid): TLC (DCM = 1, R_f = 0.7, UV 254 nm); FT-IR (neat) ν_max = 3468, 3155, 2967, 1749, 1564, 1465, 1297, 1268, 1159, 1042, 1018, 938, 846, 762, 697, 637, 527, 429 cm^-1; LCMS: m/z = 209.0 (M+H⁺); HRMS (ESI) calcd for C₇H₇F₃N₂O₂H⁺ [M+H⁺] 209.0532, found 209.0535; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 6.83 (s, 1H), 3.91 (s, 3H), 2.33 (s, 3H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -56.17; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 157.9, 150.6, 134.5, 118.2 (q, J = 263.1 Hz, CF₃), 115.8, 52.8, 13.5. 10b (colorless oil): TLC (DCM = 1, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3448, 3151, 2960, 1732, 1567, 1482, 1460, 1439, 1413, 1361, 1295, 1231, 1182, 1061, 1017, 944, 813, 783, 691, 576, 531, 427 cm^-1; LCMS: m/z = 209.0 (M+H⁺); HRMS (ESI) calcd for C₇H₇F₃N₂O₂Na⁺ [M+Na⁺] 231.0352, found 231.0367; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 6.68 (s, 1H), 3.94 (s, 3H), 2.48 (s, 3H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -57.90; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 161.8, 145.8, 142.0, 118.5 (q, J = 264 Hz, CF₃), 111.1, 52.6, 11.8 (q, ⁴J_H-F = 2.5 Hz).

4-Phenyl-1-(trifluoromethyl)-1H-pyrazole (11): (260 mg, 74% yield) was obtained as yellow oil following the general procedure. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3439, 3121, 1678, 1611, 1456, 1416, 1280, 1261, 1187, 1109, 945, 758, 694 cm^-1; LCMS: m/z = 213.0 (M+H⁺); HRMS (ESI) calcd for C₁₀H₇F₃N₂H⁺ [M+H⁺] 213.0634, found 213.0635; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 8.04 (d, J = 4.4 Hz, 2H), 7.57 – 7.49 (m, 2H), 7.47 – 7.39 (m, 2H), 7.38 – 7.31 (m, 1H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -60.39; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 141.7, 130.4, 129.2, 128.0, 126.2, 125.8, 124.3, 118.2 (q, J = 263.0 Hz, CF₃).

4-(1-(Trifluoromethyl)-1H-pyrazol-4-yl)pyridine (12): (290 mg, 82% yield) was obtained as a yellow solid following general procedure. TLC (petroleum ether/EtOAc = 1:3, R_f = 0.5, UV 254 nm); FT-IR (neat) ν_max = 3442, 3085, 3067, 1611, 1434, 1275, 1226, 1215, 1174, 1111, 1063, 962, 943, 820, 768, 688, 669, 526 cm^-1; LCMS: m/z = 214.0 (M+H⁺); HRMS (ESI) calcd for C₉H₆F₃N₃H⁺ [M+H⁺] 214.0587, found 214.0595; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 9.24 (s, 1H), 8.77 – 8.45 (m, 3H), 7.87 – 7.61 (m, 2H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -59.46; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 150.3, 142.4, 137.6, 128.3, 122.7, 120.3, 117.8 (q, J = 262.5 Hz, CF₃).

4-(1-(Trifluoromethyl)-1H-pyrazol-4-yl)pyrimidine (13): (280 mg, 79% yield) was obtained as a white solid following the general procedure. TLC (petroleum ether/EtOAc = 0:1, R_f = 0.6, UV 254 nm). FT-IR (neat) ν_max = 3447, 3075, 1601, 1572, 1431, 1286, 1200, 1123, 1081, 969, 943, 839, 780, 769, 718, 666, 575 cm^-1; LCMS: m/z = 215.0 (M+H⁺); HRMS (ESI) calcd for C₈H₅F₃N₄H⁺ [M+H⁺] 215.0539, found 215.0549; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 9.32 (s, 1H), 9.17 (d, J = 1.3 Hz, 1H), 8.84 (d, J = 5.3 Hz, 1H), 8.62 (s, 1H), 7.95 (dd, J = 1.4, 5.4 Hz, 1H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -59.61; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 158.8, 157.9, 156.4, 142.8, 130.2, 123.6, 117.6 (q, J = 262.3 Hz, CF₃), 117.5.

4-(4-Bromophenyl)-1-(trifluoromethyl)-1H-pyrazole (14): (330 mg, 68% yield) was obtained as a yellow solid following the general procedure. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.7, UV 254 nm). FT-IR (neat) ν_max = 3446, 3122, 3053, 2919, 2361, 1908, 1607, 1574, 1491, 1423, 1359, 1259, 1186, 1102, 1053, 951, 838, 765, 707 cm^-1; LCMS: m/z = 290.9 (M+H⁺); HRMS (ESI) calcd for C₁₀H₆BrF₃N₂H⁺ [M+H⁺] 290.9739, found 290.9713; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 8.03 (s, 1H), 8.01 (s, 1H), 7.55 (d, J = 8.4 Hz, 2H), 7.38 (d, J = 8.4 Hz, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -60.44; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 141.4, 132.4, 129.4, 127.7, 124.7, 124.4, 121.9, 118.1 (q, J = 262.3 Hz, CF₃).

4-(4-Methoxyphenyl)-1-(trifluoromethyl)-1H-pyrazole (15): (290 mg, 72% yield) was obtained as a white solid following the general procedure. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.7, UV 254 nm). FT-IR (neat) ν_max = 3442, 3125, 2969, 2846, 1889, 1615, 1580, 1433, 1300, 1284, 1182, 1054, 950, 836, 637 cm^-1; LCMS: m/z = 243.0 (M+H⁺); HRMS (ESI) calcd for C₁₁H₉F₃N₂OH⁺ [M+H⁺] 243.0740, found 243.0737; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.98 (s, 1H), 7.94 (s, 1H),7.44 (d, J = 6.8 Hz, 2H), 6.96 (d, J = 6.5 Hz, 2H), 3.76 (s, 3H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -60.38; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 159.5, 141.6, 127.4, 125.6, 123.6, 123.0, 118.3 (q, J = 262.8 Hz, CF₃), 114.6, 55.5.

3-Methyl-1-(trifluoromethyl)-1H-pyrazol-5-amine (16): (80 mg, 26% yield) was obtained as a white solid following the general procedure. TLC (petroleum ether/EtOAc = 0:1, R_f = 0.6, UV 254 nm). FT-IR (neat) ν_max = 3439, 2925, 2227, 1745, 1640, 1583, 1367, 1327, 1248, 1161, 1055, 1017, 845, 741, 584 cm^‑1; LCMS: m/z = 166.0 (M+H⁺); HRMS (ESI) calcd for C₅H₆F₃N₃H⁺ [M+H⁺] 166.0587, found 166.0599; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 5.35 (s, 1H), 4.54 – 3.38 (br, 2H), 2.18 (s, 3H), 1.36 (s, 1H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -58.32; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 153.6, 147.4, 119.1 (q, J = 261.1 Hz, CF₃), 91.7, 14.0.

3-Phenyl-1-(trifluoromethyl)-1H-pyrazol-5-amine (17): (210 mg, 56% yield) was obtained as a white solid following the general procedure using EtOH instead of DCM. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.6, UV 254 nm). FT-IR (neat) ν_max = 3498, 3311, 3187, 1632, 1573, 1494, 1452, 1377, 1324, 1251, 1167, 1141, 1072, 1047, 951, 763, 696 cm^-1; LCMS: m/z = 228.0 (M+H⁺); HRMS (ESI) calcd for C₁₀H₈F₃N₃H⁺ [M+H⁺] 228.0743, found 228.0759; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.86 – 7.67 (m, 2H), 7.49 – 7.32 (m, 3H), 5.86 (s, 1H), 4.23 (br s, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -58.24; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 154.9, 147.6, 132.0, 129.1, 128.7, 126.2, 119.2 (q, J = 262.3 Hz, CF₃), 88.9.

3-(Pyridin-4-yl)-1-(trifluoromethyl)-1H-pyrazol-5-amine (18) and N-(tert-butyl)-3-(pyridin-4-yl)-1-(trifluoromethyl)-1H-pyrazol-5-amine (18b): 18 (50 mg, 13% yield) and 18b (70 mg, 15% yield) were obtained as white solids following the general procedure. 18: TLC (petroleum ether/EtOAc = 1:1, R_f = 0.4, UV 254 nm); FT-IR (neat) ν_max = 3338, 3176, 2771, 1663, 1581, 1557, 1481, 1381, 1325, 1263, 1214, 1156, 1076, 1049, 958, 834, 761, 660, 598, 538, 472 cm^-1; LCMS: m/z = 229.1 (M+H⁺); HRMS (ESI) calcd for C₉H₇F₃N₄H⁺ [M+H⁺] 229.0696, found 229.0716; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 8.62 (dd, J = 4.8, 1.6 Hz, 2H), 7.72 (dd, J = 4.4, 1.6 Hz, 2H), 6.34 (s, 2H), 5.98 (s, 1H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = ‑57.60; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 151.7, 150.6, 150.2, 139.0, 120.0, 118.7 (q, J = 262.6 Hz, CF₃), 86.8. 18b: TLC (petroleum ether/EtOAc = 1:1, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3436, 3122, 2988, 1583, 1557, 1518, 1356, 1289, 1215, 1144, 1069, 951, 831, 795, 688 cm^-1; LCMS: m/z = 285.1 (M+H⁺); HRMS (ESI) calcd for C₁₃H₁₅F₃N₄H⁺ [M+H⁺] 285.1322, found 285.1319; ¹H NMR: (400 MHz, CDCl₃) δ (ppm)= 8.66 (br d, J = 5.6 Hz, 2H), 7.69 (dd, J = 4.4, 0.9 Hz, 2H), 5.90 (s, 1H), 4.26 (br s, 1H), 1.41 (s, 9H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -57.53; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 152.0, 150.2, 147.9, 139.9, 120.6, 119.3 (q, J = 262.6 Hz, CF₃), 88.2, 52.5, 29.2.

3-(4-Bromophenyl)-1-(trifluoromethyl)-1H-pyrazol-5-amine (19): (180 mg, 35% yield) was obtained as a white solid following the general procedure, using prep-TLC instead of column chromatography. TLC (petroleum ether/THF = 4:1, R_f = 0.6, UV 254 nm). FT-IR (neat) ν_max = 3504, 3342, 3245, 2920, 1639, 1588, 1369, 1331, 1147, 1110, 949, 842, 756, 744 cm^‑1; LCMS: m/z = 305.9 (M+H⁺); HRMS (ESI) calcd for C₁₀H₇BrF₃N₃H⁺ [M+H⁺] 305.9848, found 305.9851; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.64 (d, J = 8.4 Hz, 2H), 7.53 (d, J = 8.5 Hz, 2H), 5.82 (s, 1H), 4.25 (br s, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = ‑58.30 (s); ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 153.7, 147.6, 131.9, 130.1, 127.8, 123.2, 119.2 (q, J = 262.3 Hz, CF₃), 88.8.

3-(4-Bromophenyl)-N-(tert-butyl)-3-oxopropanamide (19a): (100 mg, 20% yield) was obtained as a white solid following the general procedure. The analytical data were consistent with those reported in the literature.[20] TLC (petroleum ether/THF = 4:1, R_f = 0.65, UV 254 nm). FT-IR (neat) ν_max = 3431, 3293, 3088, 2973 1685, 1637, 1552, 1426, 1395, 1362, 1332, 1247, 1072, 1008, 945, 812, 690, 613, 511, 463 cm^-1; LCMS: m/z = 298.0 (M+H⁺); ¹H NMR: (400 MHz, CDCl₃) [Note: ~1:0.16 keto:enol ratio observed; data reported for keto-tautomer only]; δ (ppm) = 7.92 – 7.84 (m, 2H), 7.68 – 7.61 (m, 2H), 6.68 (br s, 1H), 3.82 (s, 2H), 1.36 (s, 9H); ¹³C{¹H} NMR: (100 MHz, CDCl₃) [Note: ~1:0.16 keto:enol ratio observed; all major peaks are reported] δ (ppm) = 195.5, 164.5, 135.1, 132.3, 131.7, 130.3, 129.5, 127.3, 51.7, 47.1, 29.1, 28.8.

3-(4-Fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-5-amine (20): (160 mg, 39% yield) was obtained as a white solid following the general procedure, using prep-TLC instead of column chromatography. TLC (petroleum ether/DCM = 2:3, R_f = 0.6, UV 254 nm). FT-IR (neat) ν_max = 3494, 3354, 3245, 1902, 1640, 1603, 1492, 1451, 1371, 1321, 1155, 1107, 950, 787, 756 594 cm^-1; LCMS: m/z = 246.0 (M+H⁺); HRMS (ESI) calcd for C₁₀H₇F₄N₃H⁺ [M+H⁺] 246.0649, found 246.0664; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.85 ­– 7.67 (m, 2H), 7.09 (ap t, J = 8.7 Hz, 2H), 5.81 (s, 1H), 4.24 (br s, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = ‑58.28 (s, 3F), ‑112.54 (s, 1F); ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 163.4 (d, ¹J_C-F = 246.5 Hz), 153.9, 147.6, 128.3, 128.0 (d, ³J_CF = 8.4 Hz), 119.2 (q, J = 262.3 Hz, CF₃), 115.8 (d, ²J_CF = 21.5 Hz), 88.8.

4-Phenyl-1-(trifluoromethyl)-1H-pyrazol-5-amine (21): (200 mg, 63% yield) was obtained as a white solid following a modification of the general procedure, using prep-TLC instead of column and using 1.0 eq (200 mg) of cyanoaldehyde instead of 1.2 eq. TLC (petroleum ether/DCM = 1:1, R_f = 0.5, UV 254 nm). FT-IR (neat) ν_max = 3491, 3336, 3233, 3052, 2918, 2850, 1632, 1607, 1514, 1399, 1275, 1149, 1118, 927, 884, 767, 741, 618, 510 cm^-1; LCMS: m/z = 228.0 (M+H⁺); HRMS (ESI) calcd for C₁₀H₈F₃N₃H⁺ [M+H⁺] 228.0743, found 228.0759; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.65 (s, 1H), 7.49 – 7.42 (m, 2H), 7.41 – 7.35 (m, 2H), 7.35 – 7.28 (m, 1H), 4.40 (br s, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -58.39; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 142.9, 142.6, 131.5, 129.4, 127.1, 127.0, 119.2 (q, J = 262.3 Hz, CF₃), 106.6.

4-Methyl-3-phenyl-1-(trifluoromethyl)-1H-pyrazol-5-ol (22): Starting from the phenyl ester, (65 mg, 40% yield) was obtained as white solid following the general procedure (reaction time = 48h), using prep-TLC instead of column chromatography (Note: 200 mg of 3, 0.67 mmol was used). Starting from the ethyl ester, (195 mg, 48% yield) was obtained as a white solid following the general procedure (reaction time = 48h), using prep-TLC instead of column chromatography. TLC (petroleum ether/EtOAc = 4:1, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3435, 3035, 2839, 1658, 1608, 1480, 1404, 1301, 1190, 1119, 953, 773, 712, 695, 639, 488 cm^-1; LCMS: m/z = 243.0 (M+H⁺); HRMS (ESI) calcd for C₁₁H₉F₃N₂OH⁺ [M+H⁺] 243.0740, found 243.0755; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 7.68 (dd, J = 1.6, 8.0 Hz, 2H), 7.53 – 7.39 (m, 3H), 2.03 (s, 3H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -57.54; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) [Note: Due to broad peaks, not all of the ¹³C signals could be identified] δ (ppm) = 154.4 (br s), 132.1 (br s), 129.3, 128.8, 127.7, 119.0 (q, J = 260.9 Hz, CF₃), 98.1 (br s), 7.7.

5-Phenyl-2-(trifluoromethyl)-2,4-dihydro-3H-pyrazol-3-one (23): Starting from the phenyl ester, (35 mg, 46% yield) was obtained as yellow solid following the general procedure, using prep-TLC instead of column chromatography (Note: 100 mg of 3 was used). Starting from the carboxylic acid, (60 mg, 36% yield) was obtained as a yellow solid following a modification of the general procedure, using prep-TLC instead of column chromatography (Note: 220 mg of 3 was used). Starting from the ethyl ester, (188 mg, 49% yield) was obtained as a yellow solid following a modification of the general procedure, using prep-TLC instead of column chromatography. Starting from the amide, (205 mg, 54% yield) was obtained as a yellow solid following a modification of the general procedure, using prep-TLC instead of column chromatography. TLC (petroleum ether/EtOAc = 2:3, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3506, 3077, 2973, 2923, 1758, 1566, 1497, 1397, 1369, 1319, 1304, 1291, 1265, 1154, 1143, 987, 917, 878, 766, 729, 694, 650, 624, 547, 515 cm^-1; LCMS: m/z = 229.0 (M+H⁺); HRMS (ESI) calcd for C₁₀H₇F₃N₂OH⁺ [M+H⁺] 229.0583, found 229.0591; ¹H NMR: (400 MHz, CDCl₃) δ (ppm) = 7.72 (br d, J = 7.0 Hz, 2H), 7.59 – 7.36 (m, 3H), 3.79 (s, 2H); ¹⁹F NMR: (376 MHz, CDCl₃) δ (ppm) = -61.03; ¹³C{¹H} NMR: (100 MHz, CDCl₃) δ (ppm) = 169.2, 156.2, 131.7, 129.9, 129.2, 126.4, 118.3 (q, J = 262.3 Hz, CF₃), 38.7.

3-(4-Fluorophenyl)-1-(trifluoromethyl)-1H-pyrazol-5-ol (24): Starting from the phenyl ester, (45 mg, 55% yield) was obtained as white solid following the general procedure, using prep-TLC instead of column chromatography (Note: 100 mg of 3 was used). Starting from the ethyl ester, (208 mg, 51% yield) was obtained as white solid following the general procedure, using prep-TLC instead of column chromatography. TLC (petroleum ether/EtOAc = 2:3, R_f = 0.6, UV 254 nm); FT-IR (neat) ν_max = 3448, 3098, 3034, 2929, 2853, 1774, 1671, 1606, 1571, 1506, 1417, 1302, 1268, 1231, 1144, 1035, 842, 813, 735, 723, 589, 516, 472 cm^-1; LCMS: m/z = 246.9 (M+H⁺); HRMS (ESI) calcd for C₁₀H₆F₄N₂OH⁺ [M+H⁺] 247.0489, found 247.0487; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 12.73 (br s, 1H), 7.85 (dd, J = 5.6, 8.8 Hz, 2H), 7.22 (t, J = 8.8 Hz, 2H), 6.02 (s, 1H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -57.72 (s, 3F), -112.61 (s, 1F); ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 162.8 (d, ¹J_CF = 244.5 Hz), 156.2 (br s), 152.7 (br s), 128.6 (br s), 127.9 (d, ³J_CF = 8 Hz), 118.5 (q, J = 262.3 Hz, CF₃), 115.7 (d, ²J_CF = 21.3 Hz), 85.7 (br s).

3-(Pyridin-3-yl)-1-(trifluoromethyl)-1H-pyrazol-5-ol (25): Starting from the amide, (50 mg, 44% yield) was obtained as white solid after prep-HPLC, following a modification of the general procedure using TFA (5 eq) instead of TsOH; (Note: 150 mg of 3 was used). Starting from the ethyl ester, (155 mg, 41% yield) was obtained as white solid after prep-HPLC, following a modification of the general procedure (reaction time = 48h) using TFA (5 eq) instead of TsOH. TLC (EtOAc, R_f = 0.6, trailing spot, UV 254 nm); FT-IR (neat) ν_max = 3424, 3123, 2369, 1753, 1579, 1474, 1433, 1356, 1292, 1238, 1161, 1050, 948, 817, 745, 703, 652, 598, 534, 473 cm^-1; LCMS: m/z = 230.0 (M+H⁺); HRMS (ESI) calcd for C₉H₆F₃N₃OH⁺ [M+H⁺] 230.0536, found 230.0556; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 14.13 – 11.84 (br, 1H), 9.00 (d, J = 1.6 Hz, 1H), 8.59 (dd, J = 1.6, 4.8 Hz, 1H), 8.17 (td, J = 1.9, 8.0 Hz, 1H), 7.47 (dd, J = 4.6, 7.7 Hz, 1H), 6.09 (br s, 1H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) = -57.73; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 156.4 (br s), 151.0, 149.9, 146.8, 132.9, 127.7, 123.8, 118.3 (q, J = 262.3 Hz, CF₃), 85.5.

Di-tert-butyl 1-((difluoromethyl)sulfonyl)hydrazine-1,2-dicarboxylate (34): To a solution of 1 (1.15 g, 4.99 mmol, 1 eq) in DCM (20 mL) and H₂O (8 mL) was added Zn(CHF₂SO₂)₂ (4.43 g, 14.98 mmol, 3 eq) and TBHP (900 mg, 9.99 mmol, 957 µL, 70% wt, 2 eq). The mixture was stirred at 10­–20 °C for 4 hours. TLC (Petroleum ether/EtOAc = 4:1, R_f = 0.75, stained with PMA) indicated 1 was consumed completely and one major spot (more polar) formed. The reaction mixture was quenched with water (50 mL) and extracted with DCM (3 × 20 mL). The combined organic phase was washed with brine (60 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, petroleum ether/EtOAc= 1/0 to 2/1) to afford 34 (1 g, 3.54 mmol, 58% yield) as a white solid. 34: FT-IR (neat) ν_max = 3318, 2993, 2944, 1760, 1715, 1505, 1406, 1371, 1324, 1276, 1244, 1139, 1104, 1045, 820, 756, 718, 666, 620, 553, 534, 466 cm^-1; HRMS (ESI) calcd for C₆H₁₁F₂N₂O₄S^– [M-Boc]^– 245.0413, found 245.0424; ¹H NMR: (400 MHz, DMSO-d₆) [mixture of rotamers; major peaks reported] δ (ppm) = 10.22 (s, 1H), 7.21 (t, J = 52.4 Hz, 1H), 1.47 (m, 9H), 1.44 (m, 9H); ¹⁹F NMR: (376 MHz, DMSO-d₆) δ (ppm) [mixture of rotamers; major peaks reported] = -115.94, -116.63, -117.75, -118.44; ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) [mixture of rotamers, major peaks reported] δ (ppm) = 154.4, 149.4, 114.2 (t, J = 283.8 Hz, CHF₂), 86.5, 81.5, 27.8, 27.2.

Di-tert-butyl 1-(difluoromethyl)hydrazine-1,2-dicarboxylate (35): To a solution of diBoc hydrazine 3c (5 g, 21.53 mmol, 1 eq) in DCM (90 mL) was added a solution of KOH (7.25 g, 129.16 mmol, 6 eq) in H₂O (30 mL). Then TMSCF₂Br (8.74 g, 43.05 mmol, 2 eq) was added at 0 °C under N₂. The mixture was stirred at 0 °C for 4 hours. TLC (Petroleum ether/EtOAc = 4:1, R_f = 0.75, stained with PMA) indicated 3c was consumed completely and one major spot (less polar) formed. The reaction mixture was quenched with water (100 mL) and extracted with DCM (3 × 50 mL). The combined organic phase was washed with brine (200 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, petroleum ether/EtOAc = 1/0 to 2/1) to afford 35 (3 g, 10.63 mmol, 49% yield) as a white solid. 35: FT-IR (neat) ν_max = 3308, 2998, 2982, 2941, 1728, 1511, 1395, 1368, 1358, 1310, 1153, 1054, 962, 858, 810, 758, 609,469 cm^-1; LCMS: m/z = 281.1 (M-H⁺); HRMS (ESI) calcd for C₁₁H₁₉F₂N₂O₄^– [M-H⁺] 281.1318, found 281.1294; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 9.03 (br, 1H), 7.28 (t, J = 59.6 Hz, 1H), 1.46 – 1.38 (m, 18H); ¹⁹F NMR: (376 MHz, DMSO-d_6, 298 K) δ (ppm) [mixture of rotamers] = -98.04 – -106.70 (m, 2F); ¹⁹F NMR: (376 MHz, DMSO-d_6, 273+120 K) δ (ppm) = -102.11 (br s, 2F); ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 154.7, 152.0 (br s), 109.1 (t, J = 241.7 Hz, CHF₂), 82.8 (br s), 80.1, 27.9, 27.5.

Dibenzyl 1-(difluoromethyl)hydrazine-1,2-dicarboxylate (37): To a solution of 36 (10 g, 33.30 mmol, 1 eq) in DCM (120 mL) was added a solution of KOH (11.21 g, 199.79 mmol, 6 eq) in H₂O (30 mL). Then TMSCF₂Br (7.44 g, 36.63 mmol, 1.1 eq) was added at 0 °C under N₂. The mixture was stirred at 0 °C for 4 hours. TLC (Petroleum ether/EtOAc = 4:1, R_f = 0.6, stained with PMA) indicated 36 was consumed completely and one major spot (less polar) formed. The reaction mixture was quenched with water (200 mL) and extracted with DCM (3 × 100 mL). The combined organic phase was washed with brine (300 mL), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure to give a residue, which was purified by column chromatography (SiO₂, petroleum ether/EtOAc = 1/0 to 2/1) to afford 37 (4.1 g, 11.70 mmol, 35% yield) as a white solid. 37: FT-IR (neat) ν_max = 3326, 3060, 2963, 2908, 1754, 1729, 1507, 1454, 1357, 1321, 1235, 1098, 1061, 1040, 938, 738, 704, 600, 523, 482 cm^-1; LCMS: m/z = 349.1 (M-H⁺); HRMS (ESI) calcd for C₁₇H₁₅F₂N₂O₄^– [M-H⁺] 349.1005, found 349.1016; ¹H NMR: (400 MHz, DMSO-d₆) δ (ppm) = 10.32 – 9.55 (m, 1H), 7.53 – 7.15 (m, 10H), 5.45 – 4.99 (m, 4H); ¹⁹F NMR: (376 MHz, DMSO-d₆, 298 K) [mixture of rotamers] δ (ppm) = ‑98.40 – ‑106.76 (m, 2F), ¹⁹F NMR: (376 MHz, DMSO-d_6, 273+120 K) δ (ppm) = ‑101.64 (br s, 2F); ¹³C{¹H} NMR: (100 MHz, DMSO-d₆) δ (ppm) = 156.0, 153.0 (br s), 136.2, 135.3, 128.6, 128.5, 128.3, 128.0, 109.7 (t, J = 239.1 Hz, CHF₂), 68.4, 66.8.

AUTHOR INFORMATION

Corresponding Author

Christopher R. H. Hale – Chemical Development, Karuna Therapeutics – A Bristol Myers Squibb Company, 99 High Street, Floor 26, Boston, MA 02110

Authors

Vijaya B. Gondi – Chemical Development, Karuna Therapeutics – A Bristol Myers Squibb Company, 99 High Street, Floor 26, Boston, MA 02110

Bao Li, Fenglei Xie, Rui Zhang, Yaoyi Wang – WuXi AppTec Research Chemical Service, 168 NanHai Road, 10^th Avenue, TEDA, Tianjin, 300457, China

NOTES

The authors declare the following competing financial interest(s): BL, FX, RZ, and YW are employees of WuXi AppTec Research Chemical Service. VBG and CRHH are employees of Karuna Therapeutics – A Bristol Myers Squibb Company. Karuna Therapeutics – A Bristol Myers Squibb Company has a pending patent application for this work.

DEDICATION

In memory of Dr. Travis P. Remarchuk – for Science!

ASSOCIATED CONTENT

Data Availability Statement

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

Supporting Information

The Supporting Information is available free of charge at https://pubs.acs.org. Experimental procedures, characterization data, and copies of the IR, ¹H, ¹³C, ¹⁹F and 2D NMR spectroscopic data.

ACKNOWLEDGEMENTS

This work was financially supported by Karuna Therapeutics – A Bristol Myers Squibb Company.

REFERENCES

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