Regioselective [3+2]-Cycloadditions of α,β-Unsaturated Ketones with Hydrazonoyl Chloride-Derived Nitrile Imines for Stereoselective Synthesis of Pyrazolines

Dinitrogen-containing heterocycles are considered highly valuable due to their presence as privileged motifs and crucial components in many natural products and biologically active compounds. Pyrazolines, specially, are five-membered heterocycles containing dinitrogen and have garnered significant attention in the pharmaceutical industry due to their unique biological activity. These pyrazolines display a wide range of biological activities, including anti-inflammatory, anti-microbial, antifungal, analgesic, antidiabetic, antioxidant, and anticancer properties (Fig. 1).¹ For examples, aminopyrine, phenazone, and phenylbutazone are clinically approved drugs that possess potent analgesic, antipyretic and anti-inflammatory properties. Furthermore, the tyrosine kinase inhibitors, ibrutinib and axitinib, have demonstrated excellent anticancer activity. These examples highlight the versatility and potential of pyrazolines in the field of medicinal chemistry.

Figure 1. Selected examples of pyrazoline-based clinically used drugs.

In light of the importance of pyrazoline heterocycles and their influence on biological systems, considerable efforts have been made towards the development of efficient synthesis methods for a wide range of functionalized pyrazoline heterocycles.² Among the various methods available, the most commonly used method for synthesizing pyrazolines is the cyclocondensation reaction between α,β-unsaturated carbonyl compounds and hydrazine or phenyl hydrazine in acidic or basic medium.³ Additionally, the modified 1,3-dipolar cycloaddition of α,β-unsaturated carbonyl compounds with arylhydrazones has proven to be an effective method for synthesizing pyrazoline derivatives. This reaction involves the oxidative dehydrogenation of the phenyl hydrazone derivative with chloramine-T (CAT) to obtain the nitrile imine intermediate, which leads to the formation of the desired pyrazoline compound in good yields.⁴ Recently, the 1,3-dipolar cycloaddition of nitrile imines has been recognized as a highly effective approach for the synthesis of a broad range of dinitrogen-containing heterocycles from relatively simple starting materials.⁵ Nitrile imines are typically obtained through the reaction of hydrazonoyl halides with stoichiometric amounts of base. Despite its potential, the [3+2]-cycloaddition of nitrile imine with α,β-unsaturated carbonyls has received limited attention in the literature. In 2005, Sibi and co-workers reported on the asymmetric [3+2]-cycloaddition between 3-acryloyl-2-oxazolidinones and hydrozonoyl halides. The reaction was catalyzed by a chiral Lewis acid complex in combination with a compatible amine base and resulted in the synthesis of chiral dihydropyrazoles (Scheme 1-1).^5a In 2012, Roth et al. reported an Et₃N-mediated [3+2]-cycloaddition between 3-alkylidene oxindoles and hydrazonoyl bromides, resulting in the synthesis of oxindole-based spiro-pyrazoline derivatives with high regioselectivity and diastereoselectivity (Scheme 1-2).^5b The following year, Feng et al. and Stanley et al. independently developed the chiral Lewis acid-catalyzed asymmetric [3+2]-cycloaddition between 3-alkylidene oxindoles and hydrazonoyl halides.^5c,5d In 2020, Su and co-workers reported a K₂CO₃-mediated [3+2]-cycloaddition of benzoaurones and hydrazonoyl chlorides, resulting in the synthesis of spiro naphthofuranone-pyrazoline compounds with good yields (Scheme 1-3).^5f Although there have been several reports on the [3+2]-cycloaddition reaction between various α,β-unsaturated carbonyls and hydrazonoyl halides, limited studies have been conducted on the reaction between β-substituted α,β-unsaturated ketones and hydrazonoyl chlorides. Although one example of this reaction has been reported using chalcone and hydrazonoyl chloride,⁶ a comprehensive examination of this reaction has yet to be undertaken. In this work, we present our successful exploration of the [3+2]-cycloaddition reaction between β-substituted α,β-unsaturated carbonyls and hydrazonoyl chlorides, resulting in the synthesis of highly functionalized pyrazoline heterocycles with remarkable regioselectivity and diastereoselectivity (Scheme 1-4).

Scheme 1. [3+2] Cycloaddition of α,β-unsaturated carbonyls with hydrazonoyl halides.

In the presence of a base, hydrazonoyl chlorides are converted into reactive nitrile imines, where both N1 and C3 are nucleophilically activated.⁷ The [3+2]-cycloaddition reaction between α,β-unsaturated phenyl ketone 1a and hydrazonoyl chloride 2a, in the presence of a base, results in the formation of two potential regioisomers, C-adduct 3aa and N-adduct 4aa, each of which can have two diastereomers (Scheme 2). In previous literature,⁶ the preferred reaction path involved the nucleophilic attack of the carbenoid C3 carbon on the β-position of the chalcone 1a, resulting in the formation of the trans-3aa regioselective pyrazoline. However, Reddy and co-workers reported that the [3+2]-cycloaddition reaction between 1a and the nitrile imine, which was generated in situ from phenylhydrazone with chloramine-T, produced N-adduct 4aa.⁴ With this in mind, we sought to re-examined the [3+2]-cycloaddition reaction between α,β-unsaturated phenyl ketone 1a and hydrazonoyl chloride 2a and optimize the conditions for the synthesis of highly functionalized pyrazoline heterocycles in an environmentally friendly manner.

Scheme 2. Regio- and diasteroslective [3+2]-cycloaddtion of α,β-unsaturated phenyl ketone 1a and hydrozonoyl chloride 2a.

Our investigation was initiated by conducting the [3+2]-cycloaddition reaction between α,β-unsaturated phenyl ketone 1a and hydrazonoyl chloride 2a, using either the environmentally-friendly organic base Et₃N or the inorganic base Na₂CO₃, in various solvents at room temperature. The reaction performed with Et₃N in CH₂Cl₂ for 24 hours resulted in the production of [3+2]-cycloaddition compound 3aa in good yield (86%) with high 3aa/4aa selectivity (7:1) as determined by ¹H NMR analysis of the reaction mixture (Table 1, entry 1). Furthermore, the pyrazoline 3a was also formed with high diastereoselectivity (>20:1). While a slight decrease in yield was observed with toluene as the solvent, the reaction showed increased regioselectivity (entry 2). In CH₃CN, the yield was slightly increased (91%), but the ratio of 3aa/4aa decreased (entry 4). Utilizing EtOH as the solvent maintained the yield while increasing regioselectivity (entry 5). When the reaction was conducted in the presence of Na₂CO₃ as the base, it was found that the reaction hardly proceeded in solvents such as CH₂Cl₂, toluene, and THF (entries 6−7). To our delight, the reaction performed with EtOH as the solvent proceeded smoothly, resulting in the production of 3aa with a high yield of 92% and excellent selectivity (13:1 ratio 3aa/4aa, >20:1 dr; entry 10).

Table 1. [3+2]-Cycloaddition of α,β-unsaturated phenyl ketone 1a and hydrozonoyl chloride 2a^a

^aThe reactions were carried out in solvent (0.1 M) with 1a (0.1 mmol), 2a (0.12 mmol), and base (0.12 mmol).

^bIsolated yield (3aa + 4aa) after chromatographic purification.

^cDetermined by ¹H NMR analysis of the crude product.

^dNot determined.

Following the optimization of the reaction conditions, we explored the versatility and scope of hydrazonoyl chlorides in the [3+2]-cycloaddition reaction. Our results indicate that the reaction is compatible with both electrondonating and electron-withdrawing groups at the paraposition of the aryl ring in the hydrazonoyl chloride substrate. The resulting pyrazoline products, 3aa−3ae, were obtained in yields ranging from 63-99%, with the highest yield obtained for the para-bromo-substituted substrate 3ag (99% yield). Our findings also reveal that electron-donating substituents result in higher levels of regioselectivity compared to electron-withdrawing substituents. Moreover, strong electron-withdrawing groups, such as CN and CF₃, further reduce regioselectivity.

We then extended our study to the R² position of the hydrazonoyl chlorides. Regardless of the electronic nature of the substituents on the aromatic ring, the reactions with hydrazonoyl chlorides resulted in the corresponding pyrazoline products 3ai–3am with outstanding yields (89-99%) and high regioselectivities. The reaction was also successful with heteroaromatic substituted hydrazonoyl chlorides, such as 2-furyl and 2-thiophenyl, yielding high-quality products 3an and 3ao (with yields of 91% and 86%, respectively). The relative stereochemistry of pyrazoline 3 was confirmed through X-ray crystallographic analysis of 3aa.⁸

Expanding our study, we also explored the reactivity of various β-substituted α,β-unsaturated ketones 1 in the [3+2]-cycloaddition reaction. The reaction between β-aryl-α,β-unsaturated ketones 1 with an aryl substituent at R² and hydrazonoyl chloride 2 was productive and efficient. The reaction was compatible with both electron-donating and electron-withdrawing groups at the paraposition of the aryl ring of R², producing the corresponding pyrazoline derivatives 3ba–3ea with high yields (83-98%). The [3+2]-cycloaddition between 1-phenylbut-2-en-1-one (1f) and hydrazonoyl chloride 2a was successfully performed, resulting in the formation of pyrazoline 3fa with a high yield of 78% and outstanding regioselectivity (>20:1). On the other hand, the reaction between 4-phenylbut-3-en-2-one (1g) and hydrazonoyl chloride 2a still proceeded efficiently, yielding product 3ga with a yield of 85%, though with a slightly lower regioselectivity (3:1). Furthermore, γ-NHTs- and γ-OH-α,β-unsaturated ketones also showed excellent reactivity in the [3+2]-cycloaddition reaction with hydrazonoyl chloride 2a, providing the desired products in high yields with outstanding regioselectivities.

Table 2. Substrate scope of hydrazonyl chlorides^a,b

^aThe reactions were carried out with 1a (0.10 mmol), 2 (0.15 mmol), and Na₂CO₃ (0.20 mmol) in EtOH (0.1 M) at r.t.

^bIsolated yield after chromatographic purification.

^cWith Et₃N (0.20 mmol) in CH₃CN (0.1 M).

Table 3. Substrate scope of α,β-unsaturated carbonyls^a,b

^aThe reactions were carried out with 1a (0.10 mmol), 2 (0.15 mmol), and Na₂CO₃ (0.20 mmol) in EtOH (0.1 M) at r.t.

^bIsolated yield after chromatographic purification.

^cIn i-PrOH (0.1 M).

Additionally, we expanded the versatility of the [3+2]-cycloaddition reaction to include other types of β-aryl-α,β-unsaturated ketones. We found that the reaction is able to handle the presence of a TsNH group at the para-position of the aryl ring of the substituent (R²), leading to the formation of pyrazoline product 3ja with a high yield of 90%. However, when the TsNH group was located at the ortho-position, the yield of the corresponding pyrazoline product 3ka was moderate at 57%. To our delight, the reaction between β-(o-hydroxy)phenyl-α,β-unsaturated ketone 1l and β-(o-amino)phenyl-α,β-unsaturated ketone 1m, without any protective groups, proceeded smoothly and efficiently, resulting in the formation of the respective pyrazoline products 3la and 3ma with good to high yields and excellent regioselectivities. We also investigated the reactivity of various hydrazonoyl chlorides 2 in the [3+2]-cycloaddition reaction with β-(o-amino)phenyl-α,β-unsaturated ketone 1m, which produced the corresponding pyrazoline products (3mi, 3mk, 3mm, and 3mp) in moderate to good yields ranging from 50% to 86%.

To further showcase the versatility of the [3+2]-cycloaddition reaction, we performed a one-mole scale synthesis of pyrazoline product 3aa (Scheme 3-1). The reaction between 1a and 2a was conducted on a larger scale, under the optimized conditions, and produced pyrazoline 3aa with a slightly improved yield of 98% and excellent selectivity (13:1 3a/4a ratio). Additionally, the oxidation reaction using DDQ was smoothly carried out and led to the formation of pyrazole 5 with a yield of 90% (Scheme 3-2).

Scheme 3. Reaction utility.

In summary, we have successfully established an environmentally-friendly approach to synthesize highly functionalized pyrazolines through the [3+2]-cycloaddition of α,β-unsaturated ketones and hydrazonoyl chloride-derived nitrile imines using Na₂CO₃ as the base and EtOH as the solvent. This approach was applied to the [3+2]-cycloaddition of various β-substituted-α,β-unsaturated ketones, making it a versatile and practical method for the synthesis of biologically relevant pyrazolines frameworks. Further investigation is underway to explore the potential of this reaction in an asymmetric manner.

EXPERIMENTAL

General Procedure for the [3+2]-Cycloaddition of α,β-Unsaturated Ketones 1 with Hydrazonoyl Chlorides 2; To a solution of α,β-unsaturated ketone 1 (0.10 mmol) and hydrazonyl chloride 2 (0.15 mmol, 1.5 equiv) in EtOH (1.0 mL, 0.10 M) was added Na₂CO₃ (0.20 mmol, 2.0 equiv) at room temperature. After stirring for 24 h at room temperature, the resulting mixture was filtered through the plug of celite, and concentrated in vacuo. The crude residue was purified by flash column chromatography with EtOAc/hexanes as eluent to afford desired product 3.