Synthesis of polysubstituted 4-aminopyrazoles and 4-hydroxypyrazoles from vinyl azides and hydrazines

Abstract

A simple and direct synthesis of polysubstituted 4-aminopyrazoles and 4-hydroxypyrazoles from vinyl azides and hydrazines was developed. The present reactions were performed under mild conditions in moderate to excellent yields. A possible mechanism is also proposed.

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Pyrazoles represent an important class of heterocycles found in various biologically active compounds.¹ 4-aminopyrazole derivatives, in particular, exhibit various important pharmacological activities, such as inhibitors of LRRK2,² ITK,³ Jak2,⁴ and NMT.⁵ 4-Hydroxypyrazoles derivatives also possess important biological activities, such as glucagon receptor antagonist,⁶ HIV-1 integrase inhibitor,⁷ factor IXa inhibitor,⁸ and antiviral activity.⁹ There are a number of strategies to prepare substituted 4-aminopyrazoles. One common method employs cyclocondensation of diketo oximes with hydrazines to yield the nitroso pyrazoles, which can be further reduced under various conditions,¹⁰ Other methods include nitration of substituted pyrazoles followed by reduction¹¹ and conversion of 4-acyl azide pyrazole into 4-aminopyrazole under Curtius conditions.¹² However, the published syntheses of 4-hydroxypyrazoles are fairly limited. There was a report to synthesize novel 3-hydroxypyrazoles through hydrazine-mediated cyclization of Ugi products.¹³ More recently, a multistep reaction which involved halogen-metal ex-change of 4-iodopyrazoles-formylation–Baeyer–Villiger oxidation–alkaline hydrolysis to form 4-hydroxypyrazoles was reported.¹⁴

In recent years, much attention has been focused on vinyl azide, which is an important three-atom synthon to form nitrogen-containing heterocycles.¹⁵ On the other hand, hydrazines have been widely used in the construction of diverse heterocyclic scaffolds.¹⁶ In this paper, we demonstrate a simple and straightforward methodology to prepare polysubstituted 4-aminopyrazoles and 4-hydroxypyrazoles from vinyl azides and hydrazines. Herein, we would like to report the details of our research work.

Our initial experiments were performed with vinyl azide 1a and methylhydrazine sulfate 2a under different conditions (Table 1). It was found that no reaction occurred in the absence of base (Table 1, entry 1). However, the expected transformation occurred in the presence of 3 equiv. of NaOH at room temperature. The desired compound 3a was obtained as the major product with 49% yield (Table 1, entry 2). The yield was increased to 92% when 4 equiv. of NaOH was employed (Table 1, entry 3). The reaction was then tested at higher temperature but with a slight decrease in the yield (Table 1, entry4). Further, other bases were also tested for the reaction, which revealed that NaOH was the most efficient one (Table 1, entries 5–8). In order to investigate the effects of solvents on this reaction, a range of solvents including a polar protic solvent (Table 1, entry 9), polar aprotic solvents (Table 1, entry 10 and 11) and nonpolar solvent (Table 1, entry 12) were tested. But none of them showed better effects than CH₃CN. On the basis of the above studies, the most favorable reaction conditions for the formation of 3a were established.

Table 1 Optimization of reaction conditions^a

Entry	Base (equiv.)	Solvent	T (°C)	Yield^b (%)
a Reaction conditions: 1a (0.4 mmol, 1.0 equiv.), 2a (0.4 mmol, 1.0 equiv.), base (1.6 mmol), 2 ml of solvent, 8 h.b Isolated yield. The most efficient entry is highlighted in bold.
1	—	CH3CN	rt	n.r
2	NaOH(3)	CH3CN	rt	49
3	NaOH(4)	CH3CN	rt	92
4	NaOH(4)	CH3CN	50	85
5	Cs2CO3(4)	CH3CN	rt	24
6	DBU(4)	CH3CN	rt	19
7	Et3N(4)	CH3CN	rt	13
8	EtONa(4)	CH3CN	rt	Trace
9	NaOH(4)	EtOH	rt	59
10	NaOH(4)	THF	rt	71
11	NaOH(4)	DMF	rt	67
12	NaOH(4)	Toluene	rt	21

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Based on the optimal reaction condition, the scope of the reaction was studied using a series of vinyl azides 1 and hydrazines 2. As presented in Table 2, analog compounds were synthesized when R₃ was either methyl or benzyl. The low yield of pyrazole 3m might be due to steric hindrance of the benzyl group. However, when R₃ was phenyl group, only trace of the desired product was detected (3o). When at the R₁ position, both aromatic and aliphatic substituents could be tolerated (3a–3h). While at the R₂ position, various groups on the aryl ring were compatible with the reaction. When R₂ was 4-methoxyphenyl group, the reaction was relatively sluggish (3k). Meanwhile, heteroaryl motif such as thiophene at the R₂ position was successfully incorporated (3n). However, no desired product was observed when (Z)-ethyl 2-azido-3-phenylacrylate was employed probably due to the low activity of ester group.

Table 2 4-aminopyrazoles from vinyl azides and hydrazines^a

a Reaction conditions: 1 (0.4 mmol, 1.0 equiv.), 2 (0.4 mmol, 1 equiv.), NaOH (0.8 mmol, 2 equiv.), 2 mL of solvent, 8 h, rt. Isolated yield.

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To further investigate the scope of hydrazines, we then turned our attention towards the reaction between vinyl azide and hydrazine hydrate under the above conditions. Unexpectedly, we got the product of 4-hydroxypyrazole instead of 4-aminopyrazole (Scheme 1).

Scheme 1 An unexpected reaction leading to polysubstituted 4-hydroxypyrazoles.

We thus optimize the reaction conditions (Table 3). The product 4a was obtained in 45% when 1 equiv. of N₂H₄˙H₂O was employed with NaOH (2 equiv.) as the base (Table 3, entry 1). The product was obtained in a higher isolated yield when EtONa was utilized as the base (Table 3, entry 2). In further optimization of the reaction , the optimal reactivity was obtained in CH₃CN at 25 °C when 10 equiv. of N₂H₄˙H₂O was employed (Table 3, entry 4).

Table 3 Optimization of the reaction conditions^a

Entry	Base (equiv.)	Equiv. of N2H4·H2O	Solvent	Yield^b (%)
a Reaction conditions: a-azidovinyl ketone (0.4 mmol, 1.0 equiv.), base (0.8 mmol), 2 ml of solvent, 5 h.b Isolated.
1	NaOH(2)	1	CH3CN	45
2	EtONa(2)	1	CH3CN	50
3	EtONa(2)	5	CH3CN	62
4	EtONa(2)	10	CH3CN	80

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The results encouraged us to explore the scope of this unexpected reaction. As shown in Table 3, we found that a range of functionality of vinyl azides 1 could be tolerated in this reaction. Higher yields were achieved when the R₁ functionality was an phenyl ring containing an electron-withdrawing group (4a compared to 4d; 4c compared to 4e). Similar tendency of the influence of R₂-substituents of vinyl azides 1 was observed (4i compared to 4j; 4l compared to 4d). The aliphatic substituents and the furan group at the R₁ position gave lower yields than most phenyl substituents (4f, 4g and 4h) (Table 4).

Table 4 Scope of the reaction of vinyl azides and hydrazine hydrate^a

a Reaction conditions: 1 (0.4 mmol, 1.0 equiv.), hydrazine hydrate (4 mmol, 10 equiv.), NaOEt (0.8 mmol, 2 equiv.), 4 mL of solvent, 5 h, rt. Isolated yield.

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The structures of the polysubstituted 4-aminopyrazoles and 4-hydroxypyrazoles were characterized by ¹H NMR, ¹³C NMR, HRMS and NOESY (3b). Furthermore, the structure of 4d was confirmed by X-ray crystal structure analysis as shown in Fig. 1.

Fig. 1 X-ray crystal structure of 4d.

A possible reaction mechanism for the reaction process is proposed in Scheme 2. The reaction was expected to involve Michael addition–elimination of the hydrazines 2 to the vinyl azides 1 affording an active intermediate I, driven by the leaving-group ability of nitrogen. Subsequently, intramolecular condensation was caused by the base to form intermediate III. Further rearrangement of III provide the desired product 3; when the hydrazine was hydrazine hydrate, because excess water exist in the reaction system, the intermediate IV was formed by hydrolysis of III and the followed elimination of ammonia provide the desired product 4.

Scheme 2 Proposed reaction mechanism.

Conclusions

In summary, a simple and straightforward method for the synthesis of polysubstituted 4-aminopyrazoles and 4-hydroxypyrazoles was developed. The reactions appear to be useful and covenient due to readily available starting materials, experimental simplicity and mild reaction conditions.

Acknowledgements

This research was supported by the National Natural Science Foundation of China (no. 81473074, no. 81273356), National Science & Technology Major Projects for “Major New Drugs Innovation and Development” of China (2014ZX09304002-007), Program for Zhejiang Leading Team of S&T Innovation, and Alzheimer's & Aging Research Center, USA.

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1052977. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra04371a

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