NIS/CHP-mediated reaction of isocyanides with hydrazones: access to aminopyrazoles

Abstract

A NIS/CHP-mediated [4 + 1]-cycloaddition of isocyanides with 1,2-diaza-1,3-dienes generated in situ from hydrazones under metal-free conditions has been developed. This protocol provides a new, atom efficient and step efficient way to construct aminopyrazoles in good to excellent yields via formation of new C–C/C–N bonds, utilizing a catalytic amount of NIS in the presence of CHP.

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The design and development of new methods to construct heterocyclic systems attracts considerable ongoing interest due to their important activities and various useful applications.¹ During the past few decades, 1,2-diaza-1,3-dienes (DDs) have attracted great attention.^2,3 Direct C–H functionalization of sp³ C–H bonds has attracted great attention as it allows the efficient construction of new C–C/C–N/C–S bonds with atom economy and step economy.^4–6 However, reactions via direct sp³ C–H functionalization of the α-position of hydrazones to construct DDs are rare.^7,8

Aminopyrazoles are one of the most important heterocycles due to their wide bioactivities and are important building blocks in the synthesis of more important heterocycles (Fig. 1).⁹ The 3-aminopyrazole derivative Tozasertib has been shown to inhibit the activity of Aurora kinases.¹⁰ Danusertib, bearing a 1H-pyrazol-3-yl-amide scaffold, is a potential drug for the treatment of leukemias.¹¹ 5-Aminopyrazole-4-carboxamide can create inhibitors of calcium-dependent protein kinase-1.¹² In view of the synthetic value of aminopyrazoles, it is desirable to develop new methods to construct them in an efficient way. Recently, hydrazones^{2,3,7,8,13–15} and isocyanides^15–17,18 have attracted great attention as a result of their unique properties and high reactivities, and are utilized as important synthons for the synthesis of heterocycles, such as aminopyrazoles (Scheme 1).¹⁷ As a continuation of our works on isocyanide reactions¹⁸ and C–H functionalization under metal-free conditions,⁸ herein, we demonstrate a NIS/CHP-mediated [4 + 1]-cycloaddition of isocyanides with 1,2-diaza-1,3-dienes generated in situ from hydrazones via C–H functionalization under metal-free and halide substrate-free conditions. The corresponding aminopyrazoles could be obtained in good to excellent yields via formation of new C–C/C–N bonds, utilizing a catalytic amount of NIS in the presence of CHP.

Fig. 1 Selected aminopyrazoles.

Scheme 1 Synthesis of aminopyrazoles from isocyanides.

Initially, we examined the model reaction of N-tosylhydrazone 1a and tert-butyl isonitrile 2a under oxidative conditions in the presence of catalysts (for full details see the ESI†). Only trace new product was detected in the absence of catalyst or oxidant (Table 1, entries 1 and 10). To our delight, I₂ could catalyze the reaction of 1a and 2a smoothly in the presence of 2.0 equiv. TBPB to furnish the desired product 3aa in 59% LC-yield (Table 1, entry 2), of which the structure was confirmed by NMR, IR and HRMS, as well as X-ray crystal structure (see the ESI†). Inspired by this result, we evaluated several other halide source catalysts such as KI, TBAB, TBAC, TBAI, and NIS. NIS led to the best result and 3aa could be obtained in 63% LC-yield (Table 1, entries 2–7). NIS (20 mol%) combined with 2 equiv. of DTBP and O₂ could also promote the reaction well to furnish 3aa in 56% and 51% LC-yields, respectively (Table 1, entries 8 and 9). When NIS (20 mol%) and 2 equiv. of CHP were subjected to the reaction, the LC-yield of 3aa could be increased to 74% (Table 1, entry 11). Further examinations of the reaction temperature and the amount of NIS and CHP showed that 4 mol% NIS and 1 equiv. of CHP could promote the reaction efficiently at 100 °C, which afforded the desired product 3aa in 81% LC-yield (Table 1, entries 12–21). Therefore, the optimum reaction conditions are 4 mol% NIS and 1 equiv. of CHP as the oxidant in 1,4-dioxane at 100 °C for 12 h (entry 18, Table 1, 81% yield of 3aa).

Table 1 Optimization of the reaction of 1a and 2a^a

Entry	Catalyst (mol%)	Oxidant (equiv.)	Yield^b (%)
a Reaction conditions: N-tosylhydrazone 1a (0.5 mmol), tert-butyl isonitrile 2a (1.2 equiv., 0.6 mmol), catalyst, and oxidant in 3 mL of solvent at 100 °C for 12 h. b Yields were determined by HPLC analysis with biphenyl as the internal standard. c TBPB = tert-butyl peroxybenzoate. d TBAC = tetrabutyl ammonium chloride. e TBAB = tetrabutyl ammonium bromide. f TBAI = tetrabutyl ammonium iodide. g NIS = N-iodosuccinimide. h DTBP = 2-(tert-butylperoxy)-2-methylpropane. i CHP = cumene hydroperoxide. j The system was reacted at 80 °C. k The system was reacted at 110 °C. l The system was reacted at room temperature.
1	—	TBPB^c (2)	Trace
2	I2 (20)	TBPB (2)	59
3	KI (20)	TBPB (2)	57
4	TBAC^d (20)	TBPB (2)	Trace
5	TBAB^e (20)	TBPB (2)	Trace
6	TBAI^f (20)	TBPB (2)	43
7	NIS^g (20)	TBPB (2)	63
8	NIS (20)	DTBP^h (2)	56
9	NIS (20)	O2	51
10	NIS (20)	Ar	Trace
11	NIS (20)	CHP^i (2)	74
12	NIS (30)	CHP (2)	71
13	NIS (10)	CHP (2)	75
14	NIS (5)	CHP (2)	76
15	NIS (4)	CHP (2)	80
16	NIS (3)	CHP (2)	70
17	NIS (4)	CHP (3)	79
18	NIS (4)	CHP (1)	81
19^j	NIS (4)	CHP (1)	79
20^k	NIS (4)	CHP (1)	75
21^l	NIS (4)	CHP (1)	31

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With the optimized reaction conditions in hand, the scope of this transformation was subsequently investigated and the results are summarized in Scheme 2. Most of the reactions proceeded smoothly to afford the desired products in moderate to excellent yields. Typical functional groups including electron-donating and electron-withdrawing groups, such as alkyl, methoxy, NO₂, ketone, and halide, were tolerated under the same conditions. 4-Methyl-functionalized N-tosylhydrazone 1b led to the desired product 3ba in 87% yield. The reaction of 2-methyl-functionalized N-tosylhydrazone 1d afforded the desired product 3da in 57% yield due to steric effects. When halogen substituted N-tosylhydrazones 1o–t were subjected to the reaction, the corresponding products 3oa-ta were obtained in good to excellent yields (74%–97%). It should be noted that the more bulky substrates 1r and 1t could undergo the transformation to give the desired products 3ra and 3ta in 91% and 74% yields, respectively. When α-naphthyl N-tosylhydrazone 1u was applied to the reaction, 3ua could be obtained in 53% yield. To our delight, β-naphthyl N-tosylhydrazone 1v worked well to give 3va in 98% yield. In addition, the reaction with heteroaryl N-tosylhydrazones such as 1w–y could also proceed smoothly to give the desired products 3w–y in moderate to excellent yields (45%–73%). Unfortunately, the reaction of N′-(3,3-dimethylbutan-2-ylidene)-4-methylbenzenesulfono hydrazide 1z could only give the corresponding product 3za in trace yield.

Scheme 2 Substrate scope of N-tosylhydrazones 1a–z. Reaction conditions: N-tosylhydrazones 1a–z (0.5 mmol), tert-butyl isonitrile 2a (1.2 equiv., 0.6 mmol), NIS (4 mol%), CHP (1 equiv.) in 3 mL 1,4-dioxane at 100 °C. Isolated yields are shown.

Encouraged by the above results, we applied other functionalized N-tosylhydrazones 4a–f to the [4 + 1]-cycloaddition reaction with 2a (Scheme 3). When rigid substrates 4a–d were applied to the reaction, the desired products 5aa-da could be observed in low yields. However, 4-methyl-N′-(1-phenylpropylidene)benzenesulfonohydrazide 4e could only lead to a trace amount of the desired product due to its lower reactivity. The reaction of N′-(2-cyano-1-phenylethylidene)-4-methylbenzenesulfonohydrazide 4f with 2a was messy due to the presence of the CN group.

Scheme 3 Substrate scope of N-tosylhydrazones 4a–f. Reaction conditions: N-tosylhydrazones 4a–f (0.5 mmol), tert-butyl isonitrile 2a (1.2 equiv., 0.6 mmol), NIS (4 mol%), CHP (1 equiv.) in 3 mL 1,4-dioxane at 100 °C. Isolated yields are shown.

We tried to subject 4-methyl-N′-(2-phenylethylidene)benzenesulfonohydrazide 4g to the reaction with 2a under the same conditions. However, the reaction was messy (eqn (1)).

Then, we examined the substrate scope of some other N-substituted hydrazones 6a–g (Scheme 4). To our delight, the Ms, benzoyl, 2-iodobenzoyl, Cbz, and Boc substituted hydrazones 6a–e could also work well to give the desired products 7aa-ea in moderate yields (32%–57%). However, when 1-phenyl-2-(1-phenylethylidene)hydrazine 6f was used, the reaction was messy and no target product was detected. (1-Phenylethylidene)hydrazine 6g could not react under the same conditions.

Scheme 4 Substrate scope of N-substituted hydrazones 6a–g and tert-butyl isocyanide 2a. Reaction conditions: N-substituted hydrazones 6a–g (0.5 mmol), tert-butyl isonitrile 2a (1.2 equiv., 0.6 mmol), NIS (4 mol%), CHP (1 equiv.) in 3 mL 1,4-dioxane at 100 °C. Isolated yields are given.

We also investigated the substrate scope of isocyanides (Scheme 5). The reaction of 1a with benzyl isocyanide 2e performed well under the optimal conditions and led to the desired product 8ae in 56% yield. When other isocyanides 2b–d and 2f were subjected to the reaction, it could furnish 2-aminopyrazole derivatives 8ab–ad and 8af in lower yields (22%–45%). Moreover, the reaction of aryl isonitriles 2g and 2h could result in the desired products 8ag and 8ah in 21% and 19% yields, respectively.

Scheme 5 Substrate scope of N-substituted hydrazone 1a and isocyanides 2b–h. Reaction conditions: N-tosylhydrazone 1a (0.5 mmol), isonitriles 2b–h (1.2 equiv., 0.6 mmol), NIS (4 mol%), CHP (1 equiv.) in 3 mL 1,4-dioxane at 100 °C. Isolated yields are given.

To further probe the applications of our protocol, we designed the reaction of tri-hydrazone 9a with 2a (Scheme 6). To our delight, the reaction worked well to furnish the desired product 10aa in 33% yield. In addition, the photophysical properties of 10aa were investigated using UV-Vis absorption photoluminescence measurements at room temperature in CH₂Cl₂ and low temperature PL spectra of 10aa were measured in 2-MeTHF at 77 K, which indicated that its triplet energy is 2.42 eV, calculated from the phosphorescence emission peak. This result showed that the tri-arm molecule 10aa is a promising potential green-light material.

Scheme 6 NIS-catalyzed oxidative coupling reaction of 2a with N-tosylhydrazone 9a, and the photophysical characterisation of the product, 10aa.

On the basis of the literature^19,20 and the above results, a plausible catalytic cycle for this [4 + 1]-cyclization is proposed in Scheme 7. The tautomer of 1a reacts with NIS via transition state II to furnish the α-iodine-substituted intermediate III and pyrrolidine-2,5-dione. III further reacts with the pyrrolidine-2,5-dione to give 1,2-diaza-1,3-diene intermediate V and 2,5-dioxopyrrolidin-1-ium iodide IV. 1,4-Addition of tert-butyl isonitrile 2a to V leads to the intermediate VI. After subsequent cyclization of VI and further tautomerization, 3aa is formed. In addition, IV can be oxidized by CHP to regenerate NIS, which finishes the catalytic cycle.

Scheme 7 Plausible mechanism.

In conclusion, a NIS/CHP-mediated [4 + 1]-cycloaddition of isocyanides with 1,2-diaza-1,3-dienes generated in situ from hydrazones via C–H functionalization under metal-free conditions has been developed. This protocol provides a new, low-cost, atom efficient and step efficient way to construct aminopyrazoles via formation of new C–C/C–N bonds, utilizing a catalytic amount of NIS in the presence of CHP. Further studies to understand the reaction mechanism are ongoing in our laboratory.

Experimental section

General procedures

N-Iodosuccinimide (NIS) (0.02 mmol) and hydrazones (0.5 mmol) were added to a test tube. 1,4-Dioxane (3.0 mL), cumene hydroperoxide (CHP) (0.5 mmol), and isocyanides (0.6 mmol) were added via syringe. The test tube was closed. The reaction mixture was stirred at 100 °C for 12 or 24 h. Then the reactions were cooled to room temperature. Removal of solvent followed by flash column chromatographic purification using petroleum and acetone afforded the products.

Acknowledgements

We gratefully acknowledge the Natural Science Foundation of China (no. 21172162, 21372174), the Young National Natural Science Foundation of China (no. 21202111), the Ph.D. Programs Foundation of Ministry of Education of China (2013201130004), the Young Natural Science Foundation of Jiangsu Province (BK2012174), Key Laboratory of Organic Synthesis of Jiangsu Province (KJS1211), PAPD, and Soochow University for financial support.

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. CCDC 1009375. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c4qo00289j

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