Brønsted acid-promoted hydroamination of unsaturated hydrazones: access to biologically important 5-arylpyrazolines

Abstract

A novel and efficient Brønsted acid-promoted hydroamination of hydrazone-tethered olefins has been developed. A variety of pyrazolines have been easily obtained in good to excellent yields with high chemo- and regioselectivity under simple and mild conditions. This method represents a straightforward, facile, and practical approach toward biologically important 5-arylpyrazolines, which are difficult to access by previously reported radical hydroamination of β,γ-unsaturated hydrazones.

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Introduction

The functionalization of olefins is one of the most efficient and powerful strategies to rapidly construct structurally diverse and valuable molecules.^1–3 In this context, the hydroamination of olefins has drawn considerable attention from chemists. Great progress has been made in the transition-metal-catalyzed,^4,5 acid-promoted,^6,7 and miscellaneous⁸ hydroaminations of olefins.

Pyrazolines are an important class of five-membered nitrogen-containing heterocycles that present in many pharmaceuticals and bioactive molecules.^9,10 In this context, 5-arylpyrazolines often exhibit diverse and significant biological properties such as anti-cancer, anti-depressant, anti-infective, and anti-convulsant activities, etc. (Fig. 1).¹¹ Recently, the elegant synthesis of pyrazolines from β,γ-unsaturated hydrazones has been accomplished via a novel C–N bond-forming cyclization strategy by the groups of Loh, Xiao, Han, and others.^12–16 Despite recent impressive advances, the examples of the hydroamination of β,γ-unsaturated hydrazones for the construction of pyrazolines are rare.¹⁶ In 2014, Xiao and Chen et al. disclosed a novel visible-light-driven photocatalytic hydroamination of β,γ-unsaturated hydrazones, in which the generation of N-centered hydrazonyl radicals has been achieved for the first time by a visible-light photocatalytic oxidation strategy (Scheme 1a, method A).^16a Shortly afterwards, the same group developed a mild and efficient radical hydroamination of β,γ-unsaturated hydrazones for the synthesis of pyrazolines with stoichiometric amounts of PhI(OAc)₂ as the oxidant and DABCO as the base (Scheme 1a, method B).^16b In 2019, the group of Song reported the facile and metal-free access to pyrazolines from β,γ-unsaturated hydrazones via a radical pathway with the use of the oxidant TBHP in n-Bu₂O at 80 °C under N₂ atmosphere (Scheme 1a, method C).^16c The previously reported hydroaminations¹⁴ of unsaturated hydrazones represent the rapid, facile, and straightforward approaches to pyrazolines. However, the substrates employed in such hydroamination reactions are only β-unsubstituted unsaturated hydrazones, thus providing the corresponding 5-methylpyrazolines through a radical 5-exo-trig cyclization (Scheme 1a). In 2016, Chen et al. reported an impressive and elegant protocol for the preparation of 1,6-dihydropyradazines from β-aryl substituted β,γ-unsaturated hydrazones, in which a novel visible-light photocatalytic oxidative deprotonation electron transfer (ODET)/6-endo-trig cyclization/TEMPO-mediation strategy was developed (Scheme 1b).¹⁷

Fig. 1 5-Arylpyrazoline-containing bioactive molecules.

Scheme 1 Previous work and this work.

Given the fact that 5-arylpyrazolines display a broad spectrum of important biological activities, it is highly demanded to develop mild, efficient, practical, and selective methods for the construction of such type of pyrazolines. To test whether 5-arylpyrazolines could be obtained from β-aryl substituted unsaturated hydrazones, we synthesized β-phenyl substituted unsaturated hydrazones (R² = Ts, Ph, Ac, Bz) and subjected them to the previously reported radical hydroamination methods.¹⁶ Surprisingly, no desired 5-phenylpyrazoline products were observed (Scheme 1c). Based on these observations and considering the biological significance of 5-arylpyrazolines, we decided to explore new synthetic methods for the construction of the scaffolds. Inspired by the above breakthrough^12–18 and following our continuous interest in the synthesis of N-heterocycles,^15f,g we herein report a novel Brønsted acid-promoted hydroamination of β,γ-unsaturated hydrazones to afford a wide range of pyrazolines in generally excellent yields and with high chemo- and regioselectivities through an ionic pathway (Scheme 1d). It is noteworthy that the present method provides a facile, mild, efficient, and practical access to biologically significant 5-arylpyrazolines.

Results and discussion

Our studies commenced with β-phenyl substituted β,γ-unsaturated hydrazone 1a as model substrate to optimize the reaction conditions. To our delight, the desired product 5-arylpyrazoline 2a was obtained in 71% yield by the treatment of 1a with TsOH (1.0 equiv.) in CH₃CN at 50 °C for 12 h (Table 1, entry 1). Other Brønsted acids, including TsOH, TfOH, CH₃SO₃H, CF₃COOH, CH₃COOH, H₃PO₄, HCl, HBr, HI, and H₂SO₄ were also tested (Table 1, entries 2–10). Among the above acids examined, H₂SO₄ was found to be the best for this transformation, giving product 2a in 94% yield (Table 1, entry 10). The screening of solvents showed that CH₃CN was superior to other solvents, such as CH₂Cl₂, EtOH, DMF, and THF (Table 1, entries 10–14). Decreasing the amount of H₂SO₄ resulted in the lower yields of 2a (Table 1, entries 15 and 16). Additionally, the significantly decreased yield of 2a was obtained when the reaction was conducted at a lower temperature (Table 1, entry 17). No reaction occurred in the absence of a Brønsted acid, suggesting that the acid plays a crucial role in the transformation (Table 1, entry 18).

Table 1 Optimization of reaction conditions^a

Entry	Acid (equiv.)	Solvent	Yield^b (%)
a All reactions were performed with 1a (0.20 mmol) and acid (0.20 mmol) in solvent (2 mL) at 50 °C for 12 h unless otherwise noted.b Isolated yields.c H3PO4 (85 wt% in water).d HCl (36 wt% in water).e HBr (40 wt% in water).f HI (55 wt% in water).g H2SO4 (98 wt% in water).h At 25 °C. Ts = p-toluenesulfonyl, Tf = trifluoromethanesulfonyl, DMF = N,N-dimethyl formamide, THF = tetrahydrofuran.
1	TsOH (1.0)	CH3CN	71
2	TfOH (1.0)	CH3CN	82
3	CH3SO3H (1.0)	CH3CN	62
4	CF3COOH (1.0)	CH3CN	Trace
5	CH3COOH (1.0)	CH3CN	0
6^c	H3PO4 (1.0)	CH3CN	0
7^d	HCl (1.0)	CH3CN	0
8^e	HBr (1.0)	CH3CN	62
9^f	HI (1.0)	CH3CN	81
10^g	H2SO4 (1.0)	CH3CN	94
11	H2SO4 (1.0)	CH2Cl2	58
12	H2SO4 (1.0)	C2H5OH	0
13	H2SO4 (1.0)	DMF	0
14	H2SO4 (1.0)	THF	18
15	H2SO4 (0.2)	CH3CN	29
16	H2SO4 (0.5)	CH3CN	65
17^h	H2SO4 (1.0)	CH3CN	14
18	—	CH3CN	0

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With the optimized reaction conditions in hand, we subsequently investigated the generality of the Brønsted acid-promoted hydroamination reaction. As exemplified in Scheme 2, the present reaction can be extended to various β,γ-unsaturated hydrazones to give the 5-aryl or 5-alkylpyrazoline products in 60–99% yield. Substrates with either electron-donating or electron-withdrawing groups on the phenyl ring (R¹) that is attached to the C–N double bond were smoothly converted into products 2a–2j in 73–99% yield. 2-Thienyl group was also well tolerated to provide the product 2k in 81% yield. Notably, substrates bearing alkyl groups (R¹) at the C–N double bond moiety also participated in the reaction to give the corresponding products 2l–2q in 65–98% yield. The effect of the substituents (R) at the alkene moiety on the reaction was next investigated. It was found that electron-rich or electron-poor aryl groups were well tolerated under the reaction conditions, producing the 5-arylpyrazoline products 2r–2w in 85–98% yield. Furthermore, substrates bearing alkyl groups at the alkene moiety could also undergo the reaction to give the 5-alkylpyrazolines 2x and 2y in good yields. Nevertheless, no desired product 2z was obtained when R group in the substrate was changed to H atom. Additionally, the substrate bearing a gem-dimethyl moiety adjacent to C=N bond could not produce the corresponding pyrazoline product 2aa either. It is noteworthy that N-aryl, N-acetyl, and N-benzoyl substituted unsaturated hydrazones also smoothly participated in the transformation, providing the corresponding 5-arylpyrazolines 2ab–2ae in 61–92% yield.

Scheme 2 Substrate scope. ^aAll reactions were performed with 1 (0.20 mmol) and conc. H₂SO₄ (0.20 mmol) in CH₃CN (2 mL) at 50 °C for 12 h unless otherwise noted. ^b Isolated yields. ^c 3.0 mmol scale.

The structure of product 2e (CCDC 2018227) was confirmed by single-crystal X-ray diffraction analysis (Scheme 2). To demonstrate the practical application of the method, a gram-scale reaction was carried out under standard conditions and afforded product 2a in 92% yield (1.08 g) (Scheme 2).

To gain some insight into the reaction pathway, several control experiments were conducted (Scheme 3). Upon the addition of the radical scavenger butylated hydroxytoluene (BHT, 3.0 equiv.) under standard reaction conditions, the reaction still proceeded very well to give the desired product 2a in 92% yield (Scheme 3a), suggesting that a radical pathway could not be involved in this transformation. By the treatment of 1a with conc. H₂SO₄ (1.0 equiv.) in CH₃CN at 50 °C for a much shorter reaction time (0.5 h), two separable isomers Z-3 and E-3, resulting from the isomerization of the terminal olefin moiety of 1a, were obtained in 29% and 57% yields, respectively (Scheme 3b). Subsequent subjection of the isolated Z-3 or E-3 to the standard reaction conditions afforded the product 2a in 90% and 84% yields (Scheme 3c). The results indicate that the isomeric 3 could be the reaction intermediate, and an olefin isomerization process is very likely to be involved in the reaction. No product was observed when isolated Z-3 or E-3 was subjected to the standard reaction conditions in the absence of H₂SO₄ (Scheme 3d), suggesting that the Brønsted acid plays an important role in the formation of the pyrazoline product from the intermediate.

Scheme 3 Control experiments.

Based on the above experimental results and previous reports,^12–19 a plausible reaction mechanism is proposed (Scheme 4). Initial electrophilic attack on the C–C double bond of hydrazone 1 by the proton generates carbocation A, which is deprotonated to afford olefin-isomerized intermediate B.^19a–c Subsequent protonation of the hydrazone moiety of B results in cationic species C,^18a,b which undergoes a 6π-azaelectrocyclization to provide intermediate D.^19d–g Isomerization of D to E,^19a,h followed by the final deprotonation to deliver pyrazoline product 2.

Scheme 4 Proposed mechanism.

Conclusions

In summary, we have developed a novel, facile, efficient, practical, and Brønsted acid-promoted hydroamination protocol that enables the synthesis of various pyrazolines from β,γ-unsaturated hydrazones. Notably, the present method can be applied to construct the biologically significant 5-arylpyrazolines that are difficult to access by the reported radical hydroaminations of β,γ-unsaturated hydrazones. Preliminary mechanistic investigations indicated that an ionic pathway could be involved in this transformation. This reaction is characterized by simple and mild conditions, broad substrate scope, high yields, excellent chemo- and regioselectivities, and amenability to gram-scale synthesis, which makes it particularly attractive and is expected to find potential applications in organic synthesis and drug discovery.

Experimental

General information

All commercially available reagents were used without further purification. Column chromatography was performed on silica gel (200–300 mesh). ¹H NMR (400 MHz) and ¹³C NMR (100 MHz) spectra were recorded on a 400 MHz spectrometer. Chemical shifts (δ) were reported in ppm, and coupling constants (J) were given in Hertz (Hz). Data were reported as s = singlet, d = doublet, t = triplet, q = quartet, dd = doublet of doublets, m = multiplet. High-resolution mass spectra (HRMS) were recorded on an AB SCIEX Triple TOF 5600+ mass spectrometer. Melting points were uncorrected. Alkenyl hydrazone substrates 1a–1ac were prepared according to the reported methods.^17,20

General procedure for the hydroamination reaction

To a reaction tube equipped with a magnetic stir bar were added alkenyl hydrazone 1 (0.20 mmol), conc. H₂SO₄ (11 μL, 0.20 mmol), and CH₃CN (2.0 mL). The reaction mixture was stirred at 50 °C under nitrogen atmosphere for 12 h, cooled to room temperature, and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent : petroleum ether/ethyl acetate = 10 : 1) to give product 2.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful for the financial support from the National Natural Science Foundation of China (21502096), the Natural Science Foundation of Jiangsu Province (BK20150652), the Student Research Training (SRT) Project of Nanjing Agricultural University (S20190033), the Fundamental Research Funds for the Central Universities (KJQN201629), and the “333 High Level Talent Project” of Jiangsu Province.

Notes and references

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Footnotes

† Electronic supplementary information (ESI) available. CCDC 2018227 (2e) contains the supplementary crystallographic data for this paper. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/d1ra03043d

‡ H. H., N. X., and H. Z. contributed equally.

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