Cu(OTf)₂-catalyzed three-component annulation reaction: one-pot synthesis of 4,5-dihydropyrazole from aldehydes, hydrazines and alkenes

Abstract

A convenient one-pot three-component annulation process has been developed for the synthesis of 4,5-dihydropyrazole derivatives from aldehydes, hydrazines and alkenes using Cu(OTf)₂ as a catalyst. This method provides a flexible and rapid route to 4,5-dihydropyrazole.

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Dihydropyrazole has been recognized as an important framework in pharmaceutical science.¹ Many dihydropyrazole-based derivatives have been used as cannabinoid receptor 1 antagonist, monoamine oxidase inhibitors, and cancer cell inhibitors.² Due to the attractive medicinal properties of the dihydropyrazole skeleton, various efficient approaches have been developed for the preparation of these compounds.³ Nevertheless, the development of the tandem process for the one-pot synthesis of substituted dihydropyrazole directly from simple and readily available substrates is still in great demand. More recently, we reported a convenient one-pot Mannich-type/cyclization/oxidation tandem process for the synthesis of 1,3,5-substituted pyrazoles derivatives from aldehydes, hydrazines and alkynes using p-toluenesulfonic acid monohydrate (PTSA) as a multifunctional catalyst.⁴ As a result of development on the transition-metal-catalyzed reaction in our group,⁵ herein, we wish to report a highly efficient three-component annulation reaction for the synthesis of 4,5-dihydropyrazoles directly from aldehydes, hydrazines and alkenes using Cu(OTf)₂ as a catalyst. Cu(OTf)₂ effectively catalyzes the three-component annulation processes in a single reaction vessel, and a number of functionalities, such as fluoro, chloro, bromo, methyl, methoxy and hydroxyl, will be tolerated.

To identify the suitable conditions for the three-component annulation process, a series of catalysts and solvents were screened (Table 1). Initially, benzaldehyde 1a (0.5 mmol), phenylhydrazine 2a (0.5 mmol), and styrene 3a (0.6 mmol) in the presence of 20 mol% PTSA in CH₂Cl₂ at room temperature for 8 h gave the substituted dihydropyrazole 4aa in 20% yield, and the yield of 4aa was obviously higher for the tandem reaction performed in CH₃COOH (Table 1, entry 2 vs. entry 1). The combination of Cu(OTf)₂ and PTSA also produced the highly substituted dihydropyrazole 4aa in 48% yield (Table 1, entry 3). Cu(OTf)₂ provided the best results in comparison to other Lewis acids investigated and was effective in catalytic quantities (20 mol%) (Table 1, entry 5). The crystallization of compound 4aa from ethanol gave a single crystal suitable for X-ray analysis. Fig. 1 illustrates the molecular structure of the substituted dihydropyrazole 4aa.

Fig. 1 X-ray crystal structure of dihydropyrazole 4aa. The thermal ellipsoids are at the 50% probability level.

Table 1 Optimization of the formation of substituted 4,5-dihydropyrazole^a

Entry	Catalyst	T/°C	Solvent	Yield (%)^b
a Reaction conditions: benzaldehyde 1a (0.5 mmol), phenylhydrazine 2a (0.5 mmol), styrene 3a (0.6 mmol), and catalyst (20 mol % to 1a) in solvent (2 mL) for 8 h. b Isolated yield of pure product based on 1a. c The tandem reaction was carried in a 10 mL sealed tube.
1	PTSA (20 mol %)	rt	CH2Cl2	20
2	PTSA (20 mol %)	rt	CH3COOH	31
3	PTSA (10 mol %) + Cu(OTf)2 (10 mol %)	rt	CH2Cl2	48
4	Cu(OTf)2 (20 mol %)	rt	CH2Cl2	76
5	Cu(OTf)2 (20 mol %)	40 °C	CH2Cl2	89
6^c	Cu(OTf)2 (20 mol %)	60 °C	CH2Cl2	65
7	CuCl (20 mol %)	40 °C	CH2Cl2	0
8	CuCl2·2H2O (20 mol %)	40 °C	CH2Cl2	0
9	Cu(OAc)2 (20 mol %)	40 °C	CH2Cl2	0
10	Bi(OTf)3 (20 mol %)	40 °C	CH2Cl2	35
11	AgOTf (20 mol %)	40 °C	CH2Cl2	27
12	Fe(OTf)3 (20 mol %)	40 °C	CH2Cl2	18
13	Cu(OTf)2 (20 mol %)	40 °C	CH3COOH	55
14	Cu(OTf)2 (20 mol %)	40 °C	PhCl	35
15	Cu(OTf)2 (20 mol %)	40 °C	Toluene	30
16	Cu(OTf)2 (20 mol %)	40 °C	ClCH2CH2Cl	65

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Moreover, the temperature has an obvious impact on the yield of 4aa as well. Although the tandem reaction performed in CH₂Cl₂ at room temperature led to 76% yield of 4aa (Table 1, entry 4), the yield would increase to 89% when the tandem reaction is performed at reflux (Table 1, entry 5). However, when the tandem reaction was performed in CH₂Cl₂ at 60 °C, the yield of product 4aa decreased to 65% (Table 1, entry 6). Other copper catalysts, such as CuCl, CuCl₂·2H₂O, and Cu(OAc)₂, did not promote the tandem reaction (Table 1, entries 7–9). The tandem reaction was obviously restrained when using Bi(OTf)₃, AgOTf or Fe(OTf)₃ as a catalyst (Table 1, entries 10–12). The control experiment also confirmed that in the absence of Cu(OTf)₂, the reaction led to recovery of starting materials. In addition, it was found that the solvent played a crucial role in the tandem reaction (Table 1, entries 5 and 13–16). The tandem reaction was obviously restrained when it was performed in CH₃COOH, chlorobenzene, toluene and 1,2-dichloroethane (DCE) (Table 1, entries 13–16). The above investigations revealed that the best conditions for the three-component annulation reaction involved 20 mol% Cu(OTf)₂ in dichloromethane (DCM) at reflux for 8 h.

With the identification of the optimal conditions in hand, the scope of the substrates was investigated. Typical results are shown in Table 2. Aldehyde 1, either with an electron-donating or an electron-withdrawing group on the benzene ring, gave the corresponding dihydropyrazoles in good yield. Substrates 1b–1d possessing electron-donating groups at the benzene ring reacted smoothly and afforded the desired products in 83–92% yields (Table 2, entries 2–4, 15 and 20). Other aldehydes 1e–1j possessing electron-withdrawing groups at the benzene ring, such as fluoro, chloro and bromo, also reacted smoothly, providing highly substituted dihydropyrazoles (Table 2, entries 5–10, 16 and 17). In particular, the aromatic aldehydes 1d, 1h and 1j with a substituent on the ortho-position could give the corresponding 4,5-dihydropyrazoles 4da, 4ha and 4ja in high yields (Table 2, entries 4, 8 and 10). Obviously, electron-rich aldehydes provided the desired products in higher yields than electron-poor aldehydes. Additionally, aldehydes bearing a heterocyclic substituent, such as 2-thiophenaldehyde (R¹ = 2-thienyl), treated with phenylhydrazine 2a and styrene 3a in the presence of 20 mol% Cu(OTf)₂ gave the desired product 4ka in 73% yield (Table 2, entry 11). Also, aldehydes bearing polycyclic aromatic substituents, such as 1-naphthaldehyde and 2-naphthaldehyde, were treated with phenylhydrazine 2a and styrene 3a in the presence of 20 mol% Cu(OTf)₂, giving the desired product 4la and 4ma in 76% and 78% yield, respectively (Table 2, entries 12 and 13). Aromatic alkene 3b (R³ = 4–MeOC₆H₄, R⁴ = H) with an electron-donating group at the benzene ring gave the corresponding products in higher yields than alkene 3c (R³ = 4–BrC₆H₄, R⁴ = H) which possessed an electron-withdrawing group on the benzene ring (Table 2, entries 16–20). Unfortunately, cyclohexene 3d and maleic anhydride 3e, when allowed to react with benzaldehyde 1a and phenylhydrazine 2a, failed to get the desired products (Table 2, entries 21 and 22). Therefore, the results suggested that the three-component annulation reaction should be followed by the proposed pathway shown in Scheme 1, but not the 1,3-dipolar cycloaddition pathway.

Scheme 1 Proposed mechanism.

Table 2 Synthesis of substituted 4,5-dihydropyrazoles from aldehydes, hydrazines and alkenes^a

Entry	Aldehyde	Hydrazine	Alkene	Yield (%)^b
a Reaction conditions: aldehyde 1 (0.5 mmol), hydrazine 2 (0.5 mmol), alkene 3 (0.6 mmol), Cu(OTf)2 (20 mol % to 1), CH2Cl2 (2 ml), at reflux for 8 h. b Isolated yield of pure product based on 1.
1	1a: R^1 = Ph	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	89
2	1b: R^1 = 4–MeOC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	92
3	1c: R^1 = 4–MeC6H4	2b: R^2 = 4–ClC6H4	3a: R^3 = Ph; R^4 = H	83
4	1d: R^1 = 2–OHC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	85
5	1e: R^1 = 4–ClC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	80
6	1f: R^1 = 4–BrC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	81
7	1g: R^1 = 3–BrC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	82
8	1h: R^1 = 2–BrC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	78
9	1i: R^1 = 4–FC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	76
10	1j: R^1 = 2–FC6H4	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	74
11	1k: R^1 = 2-Thienyl	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	73
12	1l: R^1 = 1-Naphthyl	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	76
13	1m: R^1 = 2-Naphthyl	2a: R^2 = Ph	3a: R^3 = Ph; R^4 = H	78
14	1a: R^1 = Ph	2b: R^2 = 4–ClC6H4	3a: R^3 = Ph; R^4 = H	86
15	1b: R^1 = 4–MeOC6H4	2b: R^2 = 4–ClC6H4	3a: R^3 = Ph; R^4 = H	90
16	1f: R^1 = 4–BrC6H4	2a: R^2 = Ph	3b: R^3 = 4–MeOC6H4; R^4 = H	85
17	1h: R^1 = 2–BrC6H4	2a: R^2 = Ph	3b: R^3 = 4–MeOC6H4; R^4 = H	82
18	1a: R^1 = Ph	2a: R^2 = Ph	3b: R^3 = 4–MeOC6H4; R^4 = H	87
19	1a: R^1 = Ph	2a: R^2 = Ph	3c: R^3 = 4–BrC6H4; R^4 = H	81
20	1b: R^1 = 4–MeOC6H4	2a: R^2 = Ph	3c:R^3 = 4–BrC6H4; R^4 = H	83
21	1a: R^1 = Ph	2a: R^2 = Ph	3d: R^3 = R^4 = –(CH2)4–	0
22	1a: R^1 = Ph	2a: R^2 = Ph	3e: R^3 = R^4 = –COOCO–	0

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We propose the process detailed in Scheme 1 as the most likely mechanism for this Mannich-type/cyclization/oxidation transformation.⁶ Firstly, the reaction proceeds via an initial nucleophilic attack of hydrazine 1 on aldehyde 2 resulting in an adduct 5 which is converted into hydrazone 6 through loss of water. Secondly, the distance has been shortened by the complexation between copper(II) triflate, C=N and C=C, leading to the formation of a Mannich-type intermediate 7. This is followed by the intramolecular cyclization to afford tetrahydropyrazole 9 due to the attack of γ-NH on C=C which is activated by chelating to Cu(II), which then undergoes oxidation in the air atmosphere to afford 4,5-dihydropyrazole 4.

In summary, we have developed an effective three-component annulation reaction for the synthesis of substituted 4,5-dihydropyrazoles directly from aldehydes, hydrazines and alkenes using Cu(OTf)₂ as a catalyst. This tandem reaction proceeded smoothly without exclusion of moisture or air from the reaction mixture, which gave rapid access to a variety of substituted dihydropyrazoles.

Acknowledgements

We thank the project 973 (2011CB512005) and Guangxi Natural Science Foundation of China (2012GXNSFAA053027, 2011GXNSFD018010 and 2010GXNSFF013001) for financial support.

References

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Footnote

† Electronic supplementary information (ESI) available: Experimental section and NMR data of the prepared compounds. See DOI: 10.1039/c2ra21106h

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