Enantioselective Pyrazole Alkylation via Iridium and Squaramide Catalyzed N–H Insertion

Abstract

While pyrazoles are privileged scaffolds in medicinal chemistry, their tautomerization and Lewis-basicity pose challenges for enantioselective catalytic alkylation. Here, we report an Iridium and squaramide catalyzed N–H insertion that provides a site-selective and enantioselective route to α-pyrazole esters. An Ir catalyst promotes site-selective insertion at the less sterically hindered nitrogen (N_β); the combination of Ir and squaramide catalysts mediate asymmetric protonation with excellent enantiocontrol. These findings establish a strategy for asymmetric N–H insertion of pyrazoles, providing access to chiral nitrogen heterocycles previously inaccessible by asymmetric catalysis. This concept extends to indazole functionalization and enables the first disclosed asymmetric synthesis of a PARP7 inhibitor.

Designing drugs with three-dimensional complexity demands strategies that forge chiral centers using nitrogen heterocycles.^1–4 Among these privileged heterocycles,^5–8 pyrazoles occur in blockbuster drugs, including Celebrex, Acomplia, and Viagra. While these medicines feature N-aryl motifs, the N-alkyl pyrazole also represents an important scaffold (e.g., Jakafi and Jaypirca, Figure 1A).^6,7,9,10 In addition, the principle of “escaping from flatland” refers to increasing the number of sp³ centers to improve pharmacokinetics and efficacy.^11–14 Rather than de novo synthesis of a pyrazole, late-stage functionalization¹⁵ represents an ideal strategy for introducing chiral sp³ centers because a late stage intermediate can be diversified into analogs more efficiently.^15–28 Stereoselective strategies for pyrazole functionalization were previously limited to aza-Michael addition,^29,30 hydroamination,^31–34 and allylation³⁵ (Figure 1B). Therefore, inventing catalytic and enantioselective methods for pyrazole functionalization represents a critical challenge.^36,37

Figure 1.

Enantioselective N–H insertion into pyrazoles. (A) Inspiration for the development of enantioselective pyrazole alkylation methods. (B) Prior enantioselective methods for pyrazole alkylation. (C) Our proposed N–H insertion into pyrazoles. (D) Select prior N–H insertions.

To address this need, we envision an N–H insertion of pyrazoles with α-diazo esters (Figure 1C). A transition metal catalyst generates a carbenoid and engages in N–H insertion to form a prochiral enol, which undergoes asymmetric protonation by a chiral proton transfer catalyst (PTC) to yield α-pyrazole esters.^38,39 Previous strategies feature N–H insertions with carbazoles,⁴⁰ amines,⁴¹ and pyrazoles,⁴² which employed either chiral ligands or PTCs, notably with Pd and Cu catalysts (Figure 1D).^43–63 Pyrazoles pose distinct challenges: tautomerization generates multiple reactive N–H sites introducing site-selectivity issues,^36,64–66 and the coordination of nitrogen lone pairs can sequester catalysts, inhibiting reactivity.^31,32,66,67 During the preparation of this manuscript, Gu and Wang reported a site-selective N–H insertion of α-diazo phosphates into pyrazoles to prepare chiral phosphonates with promising enantioselectivity (up to 87% ee).⁴² Herein, we share a distinct strategy that combines (1) an Ir catalyst that enforces site-selective N–H insertion with (2) a squaramide co-catalyst that affords asymmetric protonation. This Ir and squaramide-catalyzed insertion provides access to α-pyrazole esters, previously inaccessible via enantioselective catalysis.

To initiate our study, we investigated the N–H insertion of alkyl diazo compound 1 into Ph-pyrazole 2, furnishing two α-pyrazole ester regioisomers: 3 and 4—arising from addition to the less sterically hindered nitrogen (N_β) (3) and the more sterically hindered nitrogen (N_α) (4) (Table 1). We surveyed Rh, Cu, and Pd but ultimately found that Ir was the most promising (entries 1–4). While Cu(I) showed no N-site selectivity and Pd(II) gave no reactivity, Rh(II) favored isomer 4 in a 3:1 ratio in 52% yield, potentially due to Rh generating a more reactive carbenoid due to its smaller size and increased electrophilicity—both resulting in a less selective transformation.^68,69 In contrast, Ir(I) furnished 3 in an 18:1 ratio with 88% yield (entry 4). We surveyed chiral PTCs that demonstrated high enantiocontrol in previous N–H insertions;^41,62,70,71 Catalysts S-CPA, PTC-1, or PTC-2 resulted in no enantiocontrol (entry 4–6). But squaramide PTC-3 afforded 3 in 90:10 er (entry 7). The absence of metal catalyst led to no reactivity (entry 8). The use of 2-MeTHF improved enantioselectivity to 93:7 er. Building on Zhou’s observation that steric bulk of the diazo ester enhances enantioselectivity,⁴¹ we observed a similar trend: bulkier esters delivered up to 97:3 er. Notably, greater steric bulk also improved site-selectivity furnishing >20:1 rr (entries 9–11). Extending reaction time and increasing equivalents of 1 allowed us to lower the catalyst loading to 1 mol% with >95% yield (entry 12). A tenfold increase in reaction scale afforded 3aa in 90% isolated yield, 97:3 er, and >20:1 rr. Of note, we tested Gu and Wang’s Cu(I) catalyst recently used for α-diazo phosphates and observe minimal site-selectivity (2:1 N_β:N_α) and no enantioselectivity (see Supporting Information).⁴² Our results highlight the first site- and enantioselective method to access α-pyrazole esters.

Table 1.

Reaction optimization of N–H insertion.

^aReaction conditions: 1 (0.05 mmol), 2a (0.05 mmol), [Ir(coe)₂Cl]₂ (4 mol%), CPA (6 mol%), PTC (6 mol%), 2-MeTHF (0.5 mL), 40 °C, 19 h. NMR yields using triphenyl methane as an internal standard are given. Enantiomeric ratios (er) were determined by HPLC analysis on a chiral stationary phase.

^bThe reaction was performed using 1 (0.1 mmol), 2a (0.05 mmol), [Ir(coe)₂Cl]₂ (1 mol%), CPA (1.4 mol%), PTC-3 (1.4 mol%), 2-MeTHF (0.5 mL), 40 °C, 21 h.

With this protocol, we evaluated thirty-one readily available pyrazoles and indazoles with varying substitution patterns (Table 2). The reaction proceeded with high regioselectivity (>20:1 rr) and enantioselectivity (85:15–98:2 er) across a broad range of pyrazoles. Symmetric pyrazoles 3ab–3ah undergo insertion in 50–97% yield, while electron withdrawing substituents enhancing reactivity to give a range of 70–97%. In contrast, an electron donating methyl substituent 3ac reduced yield to 53% with 95:5 er. Despite limited solubility, a morpholine analog provided 3ae in 50% yield and 91:9 er. Unsymmetric monosubstituted pyrazoles 3ai–3am and 3ap–3aw afforded products in 74–99% yield and 92:8–98:2 er; methoxy- and halogen-substituted aryl groups were well tolerated (3ap–3aw). Single X-ray crystal analysis of 3au confirms its absolute configuration. Disubstituted pyrazoles 3an–3ao gave 70–92% yield, 85:15–91:9 er, and retained excellent site-selectivity (>20:1 rr). Notably, indazoles 3ax–3aae provided 71–99% yield, 91:9–97:3 er, and >20:1 rr. Electron-donating and -withdrawing substituents at the 4-position 3ax–3az delivered 96–99% yield and 94:6–97:3 er. A 5-position electron-withdrawing group 3aaa afforded 71% yield with 97:3 er. Electron withdrawing substituents at the 7-position 3aab–3aae gave 95–97% yield and 91:9–97:3 er.

Table 2.

Investigating Scope: varying pyrazole and diazo-ester partners.

^aReaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), [Ir(coe)₂Cl]₂ (1 mol%), PTC-3 (1.4 mol%), CPA (1.4 mol%), 2-MeTHF (1.0 mL), 40 °C, 21 h. Yields of isolated products are given. Regioisomeric ratios (rr) were determined from ¹H NMR analysis of the crude reaction mixtures. Enantiomeric ratios (er) were determined by HPLC analysis on a chiral stationary phase.

^b42 h.

^cThe reaction was performed at 60 °C.

^d1.0 equiv. 1a was used.

Additionally, nine α-diazo esters (including those bearing alkyl, benzyl, alkene, carbamate, ester, and ether functional groups) 3ba, 3ea, and 3ga–3ja afforded products in 60–99% yield, 88:12–96:4 er, and >20:1 rr (Table 2). Sterically bulky diazo substrates 3ca–3da furnished reduced yields 43–65%, but similar enantioselectivity at 95:5–96:4 er. Diazo substrate 1f, bearing a more acidic β-hydrogen atom, underwent β-hydride elimination to give a mixture of product 3fa and alkene byproduct, resulting in a yield of 27% with 89:11 er. NOESY experiments support N–H insertion into the less sterically hindered nitrogen for diazo, pyrazole, and indazole substrates.

To assess their value as building blocks, we advanced these tert-butyl esters through simple derivatizations. Hydrolysis and lithium aluminum hydride reduction of 3aa provided 5 and 6, respectively with retention of stereochemistry (Figure 2A). Chiral indazole 7 represents an inhibitor of PARP7, and thus a promising lead in cancer immunotherapy studies (Figure 2B).⁷² To achieve the first asymmetric synthesis, we performed an N–H insertion with 2aae to obtain the corresponding α-indazole ester in 87% yield, 92:8 er, and >20:1 rr. Hydrolysis and deprotection afforded the carboxylic acid and free amide. Amide bond coupling provided 7 in 17% yield over 4 steps with retention of stereochemistry.

Figure 2.

Drug synthesis and product derivatization

Reaction conditions: N-H insertion: 1a (0.2 mmol), 2aae (0.1 mmol), [Ir(coe)₂Cl]₂ (1 mol%), PTC-3 (1.4 mol%), CPA (1.4 mol%), 2-MeTHF (1.0 mL), 40 °C, 21 h. Hydrolysis: MSA (5 equiv.), acetonitrile (4.0 mL), 3 h. Deprotection: TfOH (2.0 equiv.), toluene (1 mL), 40 °C, 30 min. Amide bond coupling: 2-(piperazin-1-yl)-5-(trifluoromethyl)pyrimidine (1.2 equiv.), T₃P (3.0 equiv.), pyridine (3.0 equiv.), ethyl acetate (1 mL), 16 h. Yields of isolated products are given. Regioisomeric ratios (rr) were determined from ¹H NMR analysis of the crude reaction mixtures. Enantiomeric ratios (er) were determined by HPLC analysis on a chiral stationary phase.

On the basis of our own mechanistic studies, we propose a mechanism for this Ir-catalyzed N–H insertion (Figure 3A). We first investigated the kinetic profile to establish a rate law (Figure 3A). First order dependence is observed for both diazo 1a and [Ir(coe)₂Cl]₂. An inverse order in both pyrazole 2a and squaramide PTC-3 indicates that both act as ligands to Ir and inhibit catalysis. Fractional order in pyrazole 2a may indicate that pyrazole can act as a ligand to inhibit catalysis as well as a ligand in the active catalyst species. Through ¹H NMR studies, we observe the formation of free cyclooctene (coe) in the presence of PTC-3 and pyrazole 2q (Figure 3B) indicating both can bind to the catalyst, resulting in catalyst resting state VI. The addition of an acid (e.g., CPA or citric acid, see SI for more details) enhances the rate of the reaction by facilitating dissociation of PTC-3 to generate the active Ir I complex. We observe first order dependence in CPA and observe a significant shift, or broadening when CPA is combined with either PTC-3 or pyrazole 2q in ³¹P NMR.⁷³ In the turnover limiting step, Ir-catalyst I reacts with diazo 1a to form carbenoid II. Nucleophilic attack of pyrazole 2a forms intermediate III, which is displaced by squaramide PTC-3 to give enol IV and Ir complex V. Proton transfer from V to enol IV furnishes 3aa.

Figure 3.

Proposed mechanism and experimental studies. (A) Proposed catalytic cycle for Ir catalyzed N–H insertion. (B) ¹H NMR stacked spectra of [Ir(coe)₂Cl]₂ with pyrazole 2a, CPA, or PTC-3 additives. (C) Proposed transition state for asymmetric protonation and metal swap study.

While further studies are warranted, we propose an enantiodetermining step in line with literature reports that involves enol protonation through a push-pull mechanism. The squaramide moiety donates a proton to the enol β–carbon while simultaneously accepting a proton via its amino moiety, consistent with the model proposed by Zhou (Figure 3A).^41,62 Replacing Ir(I) with Rh(I) reduced enantioselectivity of 3aa from 97:3 to 81:19 er (Figure 3C). This observation suggests that the metal is coordinated to the quinoline ring of the squaramide, in line with Zhou’s DFT model,⁶² and thus plays a role in enantioselectivity. Further mechanistic studies are underway.

Pyrazoles are prominent in medicinal chemistry, creating a demand for catalytic methods that deliver site- and stereoselective functionalizations.^3,29–35 This study introduces an Ir and squaramide catalyst combination that provides α-pyrazole esters previously inaccessible via asymmetric catalysis. Emerging carbene precursors and the modularity of this strategy point to broader opportunities for diversifying pyrazole scaffolds.^74–75

Supplementary Material

The Supporting Information is available free of charge. Experimental procedures and spectral data for new compounds (PDF).