“On water” cascade synthesis of benzopyranopyrazoles and their macrocycles

Tetrahedron Letters 59 (2018) 1501–1505

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‘‘On water” cascade synthesis of benzopyranopyrazoles and their macrocycles Sengodagounder Muthusamy ⇑, Chinnakuzhanthai Gangadurai School of Chemistry, Bharathidasan University, Tiruchirappalli 620024, India

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Article history: Received 29 January 2018 Revised 3 March 2018 Accepted 5 March 2018 Available online 6 March 2018 This paper is dedicated with best wishes to Professor Goverdhan Mehta on the occasion of his 75th birthday.

a b s t r a c t Reported herein is an intramolecular 1,3-dipolar cycloaddition strategy for rapid entry into benzopyranopyrazoles (BPP) on water medium as ‘‘open flask chemistry” approach. The in situ generation of diazo functionality in two-step sequence from the appropriate alkylated salicylaldehydes undergoes smooth [3 + 2]-cycloaddition with unactivated alkynes/alkenes furnishing benzopyranopyrazoles in good yield. This methodology was also extended for the synthesis of pyrazole incorporated macrocycles. This cascade protocol involving water medium provides an atom-economical and environment friendly approach. Ó 2018 Elsevier Ltd. All rights reserved.

Keywords: Benzopyranopyrazole Cascade reaction Diazo compound Open flask chemistry Water

Introduction Synthesis of pyrazoles remains of great interest due to their wide applications in the pharmaceutical and agrochemical industries.1,2 Currently, pyrazoles are being constantly employed as potential building blocks in drug discovery endeavours3 and also found as a inevitable key constituents of ligands for transition metals,4 receptor in supramolecular chemistry,5 liquid crystals6a and polymers.6b The most popular and classic approach for obtaining pyrazoles is the condensation of 1,3-dicarbonyl compounds with hydrazine derivatives.7 An alternative approach to the pyrazole framework is 1,3-dipolar cycloaddition of N@N dipoles onto CAC double8 or triple9 bonds. Benzopyranopyrazoles (Fig. 1) were well-known10 to have important biological activities and usually synthesized11 via intermolecular fashion involving leaving groups resulting in the emission of waste. During the last two decades, water has become a very attractive solvent for a number of efficient organic reactions at different temperature.12 Water promotes or accelerates an excellent supporting medium with numerous advantages including the ease of product isolation, non-toxicity, non-flammability, high heat capacity and

⇑ Corresponding author. E-mail address: [email protected] (S. Muthusamy). https://doi.org/10.1016/j.tetlet.2018.03.013 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.

redox stability. Many organic transformations13 were known to promote by water. A factor limiting the widespread application of on-water chemistry is the requirement for at least one reagent to be liquid in order to generate the oil-in-water emulsion that is critical for catalysis.13d Aqueous insolubility is an essential requirement for on-water chemistry as it enhanced acidity of interfacial water molecules that catalyses the reaction inside the emulsion droplet.14 Substituted pyrazoles were obtained in THFwater in the presence of Pd-catalyst15 and cyclization of diketoesters or 1,3-diketones with semicarbazide hydrochloride under ‘‘on water” conditions.15b Moreover in aqueous sulfonic16a or phosphoric acid16b catalyzed condensation reactions of hydrazines with diketones effectively yielded highly substituted pyrazoles. A Lewis acid promoted 1,3-dipolar cycloaddition of diazo compounds in water medium has been reported.8d In some cases, elevated temperature,17a,b catalysts8b,17c and the use of transition-metal catalysts8d,g,17d,8c are inevitable for these transformations. Therefore, there remains a need for identifying improved methods for the synthesis of biologically interesting benzopyranopyrazoles employing simple building blocks and minimal synthetic steps. Inspired by our ongoing interest18 in the synthesis of nitrogen containing fused heterocycles from diazo precursors, we herein report ‘‘on water” cascade reactions towards the synthesis of benzopyranopyrazoles (BPP) and pyrazole incorporated macrocycles in an intramolecular manner.

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Fig. 1. Examples of bioactive benzopyranopyrazoles.

Scheme 1. 2-(Prop-2-yn-1-yloxy)benzaldehydes.

Results and discussion We herein hypothesized an in situ generated aryl diazomethane from propargylated salicylaldehydes and their intramolecular [3+2]-cycloaddition reaction between a suitably placed terminal alkyne/alkene should form benzopyranopyrazoles. Aryl diazomethanes can be generated by the base-mediated decomposi-

tion of the corresponding aryl sulfonyl hydrazones. Hydrazones, in turn, are readily accessed from the corresponding aldehydes. To test this intramolecular dipolar cycloaddition strategy, reaction of the appropriate salicylaldehydes with propargyl bromide in DMF using potassium carbonate as a base at 0 °C to room temperature furnished19 the desired propargylated salicylaldehydes 3a–l in good yield (Scheme 1). We then examined the reaction of 3a with p-toluenesulfonyl hydrazide and K2CO3 in double distilled water (DD water) at room temperature but in vein even after 48 h and the unreacted starting material was recovered. Repeating the reaction at 60 °C furnished benzopyranopyrazole 5a in 56% yield (Table 1, entry 1). Other bases, such as NaOH, NaOMe, were less effective in promoting the reaction (Table 1, entries 2, 3). Elevating the reaction temperature to 70 °C could promote the conversion and the reaction furnished the expected product in 89% yield (Table 1, entry 4). Further increasing the reaction temperature to 90 °C, yield of the product turned lower (Table 1, entry 5). Inferior results were obtained with LiOH or tBuOK (Table 1, entries 6, 7). Lower yield obtained when the reaction was carried out in un-distilled water (Table 1, entry 8). However, combination of water with organic solvent (THF or MeOH) furnished good yield of product (Table 1, entries 9, 10). Thus, the optimized reaction conditions were found to be K2CO3 in DD water at 70 °C. Aldehydes 3 and hydrazide 4 as reactants were initially insoluble and formed a solid heap suspension ‘‘on water.” The reactants existing in a solid form began to transform into oily suspension that became homogeneous as the reactions progressed by heating and products started appearing ‘‘on water” at optimized conditions (entry 4). Although product 5a could be isolated in simple filtration, the reaction mixture was extracted with ethyl acetate and evaporating the solvent under vacuum and recrystallization from diethyl ether without column purification. Next, we examined the substrate scope of the reaction and the results are outlined in Table 2. Benzopyranopyrazoles 5b–d having methoxy substituent obtained in good yield from the appropriate precursors. The nitro-, chloro- or bromo-substituted propargylated salicylaldehydes furnished the corresponding products 5e–g. Interestingly, naphthopyranopyrazole and di-tert-butylbenzopyranopyrazole 5h,i were also synthesized in good yield. Reaction of ethoxy- or diiodo-substituted substituted salicylaldehydes afforded the expected products 5j,k in good yield, respectively. Reaction of aldehyde having both electron-withdrawing and -donating

Table 1 Optimization of reaction conditions.a

a b c d e

Entry

Solvent

Base

Temp (°C)

Time (h)

Yield (%)b

1 2 3 4 5 6 7 8 9 10

H2O H2O H2O H2O H2O H2O H2O H2O H2O-THF H2O-MeOH

K2CO3 NaOH NaOMe K2CO3 K2CO3 LiOH tBuOK K2CO3 K2CO3 K2CO3

60 60 60 70 90 70 70 70 70 70

12 24 24 12 12 24 12 24 12 12

56 31 54 89 78 39 56 60c 86d 88e

Reaction conditions: 3a (0.62 mmol), 4 (1.1 equiv), base (1.5 equiv), 2.0 mL DD water. Yield refers to the isolated and pure compound of 5a. Reaction was performed in tap water. H2O-THF (3:1 ratio). H2O-MeOH (1:1 ratio).

S. Muthusamy, C. Gangadurai / Tetrahedron Letters 59 (2018) 1501–1505 Table 2 Synthesis of benzopyranopyrazolesa 5.

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be recrystallized to confirm the structure based on single crystal X-ray analysis (Fig. 2) and its solid-state arrangements showed20 the presence of two CAH


O and a CAH


Cl intermolecular hydrogen bonding interactions. The stepwise reactions of propargylation and hydrazone formation of salicylaldehydes could be one-pot using K2CO3 as a base. Representatively, the above synthetic processes were carried out in a one-pot process using propargyl bromide and hydrazide 4. This indeed proved to be a quite efficient process but not in water medium as outlined (Scheme 3). The mechanism proposed for the above cascade process for the formation of 5 involves the reaction of aldehydes 3 with hydrazide

Fig. 2. ORTEP view of product 6b. Two molecules are present in a unit cell and one is removed for better clarity.

Scheme 3. One-pot process for benzopyranopyrazole 5b. a

Reaction conditions: 3 (1.0 equiv), 4 (1.1 equiv), base (1.5 equiv), solvent 2 mL.

substituent was carried out under the optimized conditions to yield product 5l comparatively in less yield. In all the above reactions, the diazo functionality was generated in situ under basic conditions from the initially formed hydrazone, subsequent intramolecular [3+2]-cycloaddition with tethered alkyne to afford dihydrobenzopyranopyrazoles 5 as a single product in pure form. The presence of NH group was supported by IR spectral studies. In order to confirm the structure apart from spectral and mass data, we were interested to study the X-ray analysis for a representative product. However, we failed to obtain good crystals from product 5 although all are solid. To overcome this intricacy, benzopyranopyrazoles 5b,f were subjected with Boc-anhydride in the presence of triethylamine and a catalytic amount of N,N-dimethylaminopyridine to afford Boc-protected benzopyranopyrazoles 6a,b (Scheme 2). The product 6b could successfully

Scheme 2. Derivatization of 5b,f.

Scheme 4. Plausible mechanism for the formation of 5.

Scheme 5. Reactions of alkene-tethered aldehydes.

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zole incorporated macrocycles via an intramolecular 1,3-dipolar cycloaddition in a single step operation under mild conditions, starting from readily available starting materials. The reaction does not require the assistance of any catalyst. This concise, step-economical tandem process should be complement to previously reported methods for this important class of compounds. Acknowledgments

Fig. 3. ORTEP view of compound 8b.

This research was supported by the Department of Science and Technology – Science and Engineering Research Board (DST-SERB), New Delhi (EMR/2016/003663). We thank DST, New Delhi for providing 400 MHz NMR and HRMS facility under FIST program and Alexander von Humboldt Foundation, Germany for FT-IR equipment donation. C.G. thanks UGC-BSR, New Delhi, for a fellowship. A. Supplementary data Supplementary data associated with this article can be found, in the online version, at https://doi.org/10.1016/j.tetlet.2018.03.013. References

Scheme 6. Synthesis of pyrazole incorporated macrocycles 12.

4 forms hydrazone A. Then, the reaction of A with K2CO3 generates a diazo compound B. Subsequent intramolecular [3+2]-cycloaddition with terminal alkyne of B forms 3H-pyrazole C. Then, aromatization17e by base catalyzed proton transfer of C produced benzopyranopyrazoles 5 (Scheme 4). To assess further scope of the reaction, the above cascade process was successfully extended to unactivated alkenes. Towards this, reaction of allylated salicylaldehydes 7 produced tetrahydropyranopyrazoles 8 under the optimized reaction conditions (Scheme 5). Unlike the reactions of alkynes as shown in Table 2, products 8 obtained using alkenes 7 did not involve in any aromatization step. The absence of NH group was supported by IR spectral studies. Representatively, the structure of naphthyl derivative 8b was unequivocally confirmed by single-crystal X-ray analysis (Fig. 3) and its solid-state arrangements showed20 the presence of three CAH/p intermolecular hydrogen bonding interactions. Further, this water mediated cascade methodology also appears to have considerable scope in preparing a variety pyrazole incorporated macrocycles. Towards this, a careful O-alkylation of salicylaldehyde 1a with dibromoalkanes in the presence of K2CO3/DMF yielded bromobenzaldehyde 9 as the major product with a negligible amount of bis-alkylated product. Subsequent O-alkylation of 9 with alkyne tethered hydroxy benzoate 10 using K2CO3/DMF conditions furnished the appropriate alkyne tethered aldehydes 11a–c in good yield (Scheme 6). Reaction of 11 with p-toluenesulfonyl hydrazide and K2CO3 in double distilled water afforded the desired pyrazole incorporated macrocycles 12a–c in good yield and products 12 were characterized based on their spectral data. Conclusion In conclusion, we have developed an efficient ‘‘On water” cascade strategy to synthesize benzopyranopyrazoles (BPP) and pyra-

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