An unexpected three-component reaction of 2-alkylenecyclobutanone and N′-(2-alkynylbenzylidene)hydrazide with water

Abstract

The generation of 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids via a silver(I)-catalyzed three-component reaction of 2-alkylenecyclobutanone and N′-(2-alkynylbenzylidene)hydrazide with water is reported. This unexpected transformation proceeds through 6-endo cyclization, [3 + 2] cycloaddition, and rearrangement, leading to 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids in good yields.

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Introduction

Efficient approaches for the generation of heterocycles are undoubtedly one of the most important areas in organic synthesis.¹ The rational design of substrates with multi-reactive sites is the key point for the successful transformation. Alkylenecyclopropane is a representative due to its ring strain and high reactivity.² However, less attention has been paid to alkylenecyclobutane. It might be due to its much lower reactivity, compared with alkylenecyclopropane. To improve it, Yu and co-workers reported the synthesis of 2-alkylenecyclobutanone and its application in (PhSe)₂-catalyzed Baeyer–Villiger oxidation.³ An sp² ketonic carbon was installed in the ring system. During the reaction process, selective C–C bond cleavage and rearrangement were observed. From the structure of 2-alkylenecyclobutanone (Fig. 1), its versatile reactivity through ring cleavage, ring expansion, and cycloaddition reaction could be expected, which attracted our great interest. Therefore, we initiated a program for the exploration of the transformations of 2-alkylenecyclobutanones.

Fig. 1 2-Alkylenecyclobutanone and N-imide ylide.

Recently, we have witnessed the progress of N-imide ylides (Fig. 1), which are used for incorporating nitrogen atom into molecules for the synthesis of N-containing compounds.⁴ Among the N-imide ylides, we identified that isoquinolinium-2-yl amide generated in situ from N′-(2-alkynylbenzylidene)hydrazide was a useful building block for further [3 + 2] cycloaddition.⁵ Inspired by the chemistry of 2-alkylenecyclobutanone, we envisioned that 2-alkylenecyclobutanone would be utilized as a partner as well in the reaction of isoquinolinium-2-yl amide. A spark of [3 + 2] cycloaddition would be ignited under proper conditions. The following C–C bond cleavage with the ring-opening of cyclobutanone would be anticipated. Therefore, we started to explore the feasibility of the reaction of 2-alkylenecyclobutanone with isoquinolinium-2-yl amide formed in situ from N′-(2-alkynylbenzylidene)hydrazide.

Results and discussion

The initial study was performed for the reaction of 2-alkylenecyclobutanone 1a with N′-(2-alkynylbenzylidene)hydrazide 2a in the presence of silver triflate (10 mol%) as a catalyst at 80 °C in air. Interestingly, an unexpected result affording 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acid 3a was obtained although the yield was low. The structure of compound 3a was unambiguously identified via X-ray crystallography analysis (see ESI‡). We reasoned that the desired [3 + 2] cycloaddition and ring-opening reaction of 2-alkylenecyclobutanone occurred, and an unexpected construction of a carboxylic acid group via nucleophilic attack of water to the intermediate took place subsequently. Thus, a privileged skeleton of pyrazolo[5,1-a]isoquinoline with a carboxylic acid group was successfully synthesized. It is well known that the introduction of hydroxyl and carboxylic acid groups into small molecules makes significant sense in pharmaceuticals due to their ability of increasing the solubility in aqueous system.⁶ For example, Sipoglitazar containing pyrazolylpropanoic acid was discovered as a pan PPAR agonist.⁷ We have found that compounds with the core of pyrazolo[5,1-a]isoquinoline showed promising activities as CDC25B inhibitor, TC–PTP inhibitor, and PTP1B inhibitor.⁸ We anticipated that enhanced biological activities might be exhibited in the further screening if pyrazolo[5,1-a]isoquinolines incorporated with a carboxylic acid could be obtained efficiently.

At the outset, the reaction conditions were optimized (Table 1). As the influence of base was crucial for the reaction, different bases were then screened. A trace amount of the desired product 3a was detected when K₂CO₃ was utilized as the base (Table 1, entry 1). The yield was increased when the base was changed to Na₂CO₃, NaHCO₃, KOAc, NaHSO₃, DABCO, or DMAP (Table 1, entries 2–7). Pyridine was in favour of the transformation to provide the final product in 58% yield (Table 1, entry 8). Moreover, 2,6-dimethylpyridine seemed to be the best choice for the conversion to enhance the yield to 74% (Table 1, entry 9). Further investigation of solvents were carried out and no better results were found for the transformation, which proved that DCE was the best one (Table 1, entries 10–15). The yield was reduced when the reaction temperature was elevated (Table 1, entry 16). Lower temperature hindered the conversion to afford the desired product 3a in 36% yield (Table 1, entry 17).

Table 1 Initial studies for the three-component reaction of 2-alkylenecyclobutanone 1a, N′-(2-alkynylbenzylidene)hydrazide 2a and water

Entry	Base	Solvent	T (°C)	Yield^a (%)
a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 2a.
1	K2CO3	DCE	80	Trace
2	Na2CO3	DCE	80	40
3	NaHCO3	DCE	80	43
4	KOAc	DCE	80	41
5	NaHSO3	DCE	80	45
6	DABCO	DCE	80	33
7	DMAP	DCE	80	43
8	Pyridine	DCE	80	58
9	2,6-Dimethylpyridine	DCE	80	74
10	2,6-Dimethylpyridine	MeCN	80	43
11	2,6-Dimethylpyridine	EtOH	80	57
12	2,6-Dimethylpyridine	Toluene	80	32
13	2,6-Dimethylpyridine	Dioxane	80	35
14	2,6-Dimethylpyridine	DMSO	80	Trace
15	2,6-Dimethylpyridine	AmylOH	80	41
16	2,6-Dimethylpyridine	DCE	100	50
17	2,6-Dimethylpyridine	DCE	50	36

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With the optimized reaction conditions in hand, further exploration of the reaction scope was then carried out. The results were displayed in Table 2. Reactions of 2-alkylenecyclobutanones with different R¹ groups were investigated and no obvious difference was observed. The transformation proceeded smoothly to provide the corresponding products when 2-alkylenecyclobutanones 1 attached with electron-donating group or electron-withdrawing group on the aromatic ring were utilized in the reactions. For instance, methyl and halo groups were all compatible to this transformation. It was notable that strong electron-withdrawing groups (such as trifluoromethyl and nitro groups), strong electron-donating groups (OMe) and heterocyclic substitutes had no big effect for the outcome. Additionally, N′-(2-alkynylbenzylidene)hydrazides 2 with alkyl groups (R³) also had high reactivity to fulfill the conversion as expected. Among these conversions, it was found that the desired products could also be obtained in moderate yields when R³ were alkyl groups. Various N′-(2-alkynylbenzylidene)hydrazides 2 with other substitutes were examined, which showed that this transformation could undergo well to provide the desired compounds with high efficiency and good functional group tolerance in moderate to good yields.

Table 2 Scope exploration of the three-component reaction of 2-alkylenecyclobutanone 1, N′-(2-alkynylbenzylidene)hydrazide 2 with water^ab

a Isolated yield based on N′-(2-alkynylbenzylidene)hydrazide 2.b Reaction conditions: N′-(2-alkynylbenzylidene)hydrazide 2 (0.5 mmol, 1.0 equiv.), 2-alkylenecyclobutanone 1 (1.0 mmol, 2.0 equiv.), H₂O (20.0 equiv., 0.18 mL), 2,6-dimethylpyridine (2.0 equiv.), AgOTf (10 mol %), DCE (4.0 mL), 80 °C.

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Based on the above results, a possible mechanism was proposed as shown in Scheme 1. We reasoned that the key intermediate isoquinolinium-2-yl amide A generated in situ from N′-(2-alkynylbenzylidene)hydrazide 2 in the presence of AgOTf would go through [3 + 2] cycloaddition with 2-alkylenecyclobutanone 1 to afford intermediate B. The subsequent elimination of tosyl group⁹ and following deprotonation would provide intermediate E. Nucleophilic attack of water to compound E would promote the ring-opening transformation in the presence of a base with the cleavage of C–C bond. The final oxidation in air would generate the corresponding product 3.

Scheme 1 A possible mechanism for the generation of compound 3.

Conclusions

In conclusion, we have described the generation of 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids via an unexpected silver(I)-catalyzed three-component reaction of 2-alkylenecyclobutanone, N′-(2-alkynylbenzylidene)hydrazide with water. This transformation proceeds through 6-endo cyclization, [3 + 2] cycloaddition, and rearrangement, leading to 3-(pyrazolo[5,1-a]isoquinolin-1-yl)propanoic acids in good yields. The incorporation of carboxylic acid into the scaffold of pyrazolo[5,1-a]isoquinoline would make the molecules interesting for further biological evaluations.

Acknowledgements

Financial support from National Natural Science Foundation of China (No. 21372046) and the Science & Technology Commission of Shanghai Municipality (No. 12JC1403800) is gratefully acknowledged.

Notes and references

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Footnotes

† Dedicated to Prof. Xue-Long Hou on the occasion of his 60^th birthday.

‡ Electronic supplementary information (ESI) available. CCDC ​1409399. For ESI and crystallographic data in CIF or other electronic format see DOI: 10.1039/c5ra17787a

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