Copper(ii) oxide nanoparticles as a highly active and ...

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Copper(II) oxide nanoparticles as a highly active and reusable heterogeneous catalyst for the construction of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives under solvent-free conditions† Mudumala Veeranarayana Reddy and Yeon Tae Jeong* An efficient, highly active and resalable copper oxide nanoparticle catalyzed a regioselective cascade synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives via three-component domino reactions of aldehydes, alkynes and 3-methyl-1-phenyl-1H-pyrazol-5-amine under solvent-free conditions. Good to

Received 8th September 2016 Accepted 25th October 2016 DOI: 10.1039/c6ra22445h www.rsc.org/advances

excellent yield, short reaction times, cost effectiveness; environmental friendliness, easy workup, and a recyclable catalyst are the important features of this protocol. This is the first endeavor towards the synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives from 3-methyl-1-phenyl-1H-pyrazol-5amine, alkynes and aldehydes.

Nowadays, nanocatalysis has become more and more important as a key green technology for the sustainable production of chiral and non-racemic organic compounds and also to synthesize biologically important organic molecules in a highly enantioselective manner using such novel catalytic systems.1 In addition, the nanocatalysts might provide practical advantages such as easy separation from the reaction mixture, high yield, high thermal stability, good structural stability and efficient recycling. In this context, copper oxide nanoparticles (CuO NPs) received considerable attention due to their exclusive chemical and physical properties such as high-surface-area resulting in high catalyst loading capacity, ease of handling, non-volatility, and non-ammable, readily available, inexpensive, high thermal stability, outstanding stability heterogeneous supports for catalysts, easily separated from the reaction products for further reusability. Despite its great importance, a few publications are reported in the literature for its catalytic activity in various organic transformations to get highly selective products.2 On the other hand, synthetic organic chemistry has developed efficient and versatile methods for the synthesis of diverse and complex heterocyclic molecules with excellent regio, chemo, diastereo, and enantioselectivity. Multi-component reactions (MCRs), in which more than two reactants combine in a sequential manner, have been widely used as an inuential approach in the total synthesis of natural

Department of Image Science and Engineering, Pukyong National University, Busan, 608-737, Korea. E-mail: [email protected]; Fax: +82-51-629-6408; Tel: +82-51629-6411 † Electronic supplementary information (ESI) available: All compounds NMR spectra were provided as supplementary data. See DOI: 10.1039/c6ra22445h

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products, pharmaceuticals, diagnostics, agrochemicals and other important materials.3 In these MCRs offer signicant advantages, such as, generation of multiple stereocenters with a high efficiency and atom economy, reduction of synthetic steps, waste production, and energy consumption, economies of time and labor, enhancement in the rate of reaction, and avoiding the complicated purication processes and tedious protection and deprotection of functional groups.4 The above merits make MCRs suitable for the synthesis of sustainable and diversity-oriented heterocyclic molecules from readily available starting materials.5 On the third hand, in recent years, a great deal of observation has been given to the synthesis of polyheterocyclic skeletons, which is endorsed to their comprehensive biological activities in the eld of biological/medicinal/material science, pharmaceuticals and others.6 Amongst these, pyrazolo[3,4-b]pyridines are polyheterocyclic molecules frequently found in various natural products. These molecules have attracted signicant interest owing to their wide range of biological activities such as anti-tubercular activity, anti-microbial agents, Alzheimer's disease, anti-cancer, anti-inammatory, anti-viral, antimalarial, cardiovascular, CNS depressant, neuroleptic, tuberculostatic and anti-oxidant activities.7 Some analogs have been also found to act as anti-proliferative agents, inhibitors of glycogen synthase kinase-3 and potent antitumor agents.8 Due to their extensive biological activities, pyrazolo-[3,4-b]pyridine derivatives may be prepared via some classical methods, also includes the treatment of 5-aminopyrazole and substituted a,bunsaturated compounds and other methods.9 Nevertheless, most of these methods have one or more drawbacks, such as the use of expensive catalysts, hazardous organic solvents, lower yields, prolonged reaction time, harsh reaction conditions and

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Scheme 1 Synthesis of 6-(4-bromophenyl)-4-(4-chlorophenyl)-3methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine (4a).

poor selectivity. Therefore, it is an essential area to further develop as an efficient and environmentally benign approach for building this type of heterocyclic compound is of prime importance. To the best of our knowledge, synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives via C–H bond activation followed by C–C bond formation through intramolecular cyclization in the presence of CuO NPs catalyst system have not yet been explored. In continuation of our work in the development of a new methodology for heterocyclic compounds synthesis via MCRs under heterogeneous catalysts,10 herein, we described a simple and efficient methods for the construction of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives through onepot three-component reaction of 3-methyl-1-phenyl-1Hpyrazol-5-amine (1), alkynes (2a–d) and aldehydes (3a–h) catalyzed by CuO NPs under neat conditions at 80 C (Table 2). Our initial investigation to realize this new route for phenyl1H-pyrazolo[3,4-b]pyridine derivatives focused on the MCRs of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1, 1 mmol) with 4-bromobenzaldehyde (2a, 1 mmol) and 4-chloro-1-ethynylbenzene (3a, 1 mmol) as model substrates (Scheme 1). With the above

Table 1

Optimization of reaction conditions for the synthesis of 4aa

Entry

Catalyst (mol%)

Solvent (mL)

Tem ( C)

Time (min)

Yieldb (%)

1 2 3 4c

CuO NPs (5) CuO NPs (5) CuO NPs (5) CuO NPs (10)

Neat Neat Neat Neat

RT 80 100 80

600 150 200 90

5 6 7 8 9 10 11 12 13 14 15 16 17

CuO NPs (15) CuO NPs (10) CuO NPs (10) CuO NPs (10) CuO (10) CuCl2 (10) Cu(OTf)3 (10) Cu(OAc)2 (10) CuO NPs (10) CuO NPs (10) CuO NPs (10) CuO NPs (10) CuO NPs (10)

Neat Neat Neat Neat Neat Neat Neat Neat MeOH (5) MeCN (5) THF (5) DMF (5) Toluene (5)

80 RT 60 100 80 80 80 80 60 80 60 120 100

90 150 120 90 125 140 120 142 225 180 220 225 190

45 80 82 95, 93, 92, 90 95 65 85 95 85 72 84 74 70 81 55 65 73

a

Reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1, 1 mmol) with 4bromobenzaldehyde (2a, 1 mmol) and 4-chloro-1-ethynylbenzene (3a, 1 mmol). b Isolated yield. c Catalyst was reused four times.


reactants, we have conducted the reaction at RT in the presence of 5 mol% of CuO NPs under solvent-free conditions for 10 h. Aer completion of the reaction, 4a was isolated in 45% yield (Table 1, entry 1) which was conrmed by the characterization of NMR and HRMS. Encouraged by the aforementioned result, we commenced to investigate the other parameters of the reaction and the representative results are shown in Table 1. To our gratifyingly, when changing reaction temperature from RT to 80 C, the reaction proceeded rapidly to obtain the desired product in 80% within 150 min (Table 1, entry 2). In our endeavor to further increase the yield of 4a, the experiment was investigated at 100 C but we couldn't obtain further better yield even prolong reaction time (Table 1, entry 3). Subsequently, we screened the amount of CuO NPs catalyst on model reaction at various temperatures and results are summarized in Table 1. To our surprise, the reaction occurred to afford the desired product 4a in excellent yield (95%) for 90 min with 10 mol% of CuO NPs at 80 C (Table 1, entry 4). To conrm the catalytic activity of the CuO NPs a comparison study was examined with various copper metal catalysts such CuO, CuCl2, Cu(OTf)3, Cu(OAc)2 under neat conditions at 80 C, and we observed that the desired product 4a was obtained in moderate to good yields (Table 1, entries 9–12). Next, the model reaction has ben studied the effect of different solvents, like MeOH, MeCN, THF, DMF, and toluene in the presence of 10 mol% of CuO NPs at various temperatures (Table 1, entries 13–17). In our observation at most of the solvent, conditions found that the rate of reaction was lower and desired product was obtained in moderate yield. We observed that the solvent-free condition provided a superior yield in short reaction time when compared with that of other solvents (Table 1, entry 4). With these overall results demonstrated that 10 mol% of CuO NPs under solvent-free conditions at 80 C are optimized reaction conditions for the synthesis of 4a with high yield and shorter reaction time. On the other hand, from green chemistry point-of-view, recyclability is one of the vital concerns in metal catalysis. In this connection, herein, we examined the reusability of CuO NPs on model reaction. Aer the completion of the reaction, the catalyst was separated by centrifugation using ethyl acetate as a solvent and washed three times with water and methanol and dried in an oven at 80 C. Aer that the dried catalyst could be reused in four consecutive runs without the loss of signicant activity (Table 1, entry 4), which conrmed that CuO NPs was highly active, stable and recyclable up to the four runs without loss of signicant activity. The optimized reaction conditions were then evaluated for library synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives (4a–y) employing 3-methyl-1-phenyl-1H-pyrazol-5-amine (1), with various phenyl acetylenes (2a–d) and different aldehydes (3a–h) and results are summarized in Table 2. The reaction occurred well in all these case and expected products were obtained in excellent yields. A variety of functional groups substituted on the aromatic ring of the aldehydes, including methoxy, ethoxy, isopropyl and methyl have preceded the reaction smoothly and resulted in the corresponding products in good to excellent yields. The halogen-containing aldehydes

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Table 2

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Synthesis of phenyl-1H-pyrazolo[3,4-b]pyridine derivatives (4a–y)a

Entry

R

R1

Product

Time (min)

Yieldb (%)

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25

4-Br-C6H4 4-CN-C6H4 4-Me-C6H4 4-N(CH3)2-C6H4 4-OEt-C6H4 4-OMe-C6H4 4-CH-(CH3)C6H4 3-4-5-OMe-C6H2 2-Br-C6H4 2-F-5-Br-C6H3 4-CN-C6H4 4-F-C6H4 4-CH-(CH3)C6H4 4-OH-C6H4 4-OEt-C6H4 2-5-Me-C6H3 3-Br-C6H4 3-Cl-C6H4 2-6-Me-C6H3 3-F-C6H4 3-OMe-C6H4 4-CN-C6H4 4-CH-(CH3)C6H4 4-OEt-C6H4 3-4-5-OMe-C6H2

4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 4-Cl 3-OMe 3-OMe 4-Br 4-Br 4-Br 4-Br 4-Br H H H H H H H H H H

4a 4b 4c 4d 4e 4f 4g 4h 4i 4j 4k 4l 4m 4n 4o 4p 4q 4r 4s 4t 4u 4v 4w 4x 4y

90 92 85 102 85 96 105 98 105 110 95 97 106 99 100 101 92 98 105 96 106 104 91 92 90

95 93 95 92 96 93 94 93 90 91 92 91 92 92 95 90 91 90 89 92 94 92 93 94 95

a

Reaction of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1, 1 mmol), aldehydes (2, 1 mmol), alkynes (3, 1 mmol) catalyzed by CuO NPs under solventfree conditions at 80 C. b Isolated yield.

such as –Cl, –Br, and –F were also subjected to the reaction conditions, and obtained in good to excellent yields of the desired products. Subsequently, the scope of alkynes was investigated and it was found that substituted phenylacetylene bearing –OMe, –Br, –Cl were absolutely appropriate substrates for this transformation, and the desired products were obtained in moderate to excellent yields. On basis of the results, we proposed the possible reaction mechanism for this novel MCRs methodology (Scheme 2). At rst, the imine, 5, was formed in situ from 3-methyl-1-phenyl1H-pyrazol-5-amine (1) and the aldehydes (2a–d) and then it follows the Diels–Alder type cycloaddition with Lewis acid CuO NPs catalyzed terminal acetylides (3a–h) and resulted in a Cu coordinated intermediate 6. Which on then undergoes an oxidative removal of catalyst and followed by aromatization leading to the formation 4.

Finally, for further justication of the usage of CuO NPs catalyst, we also prepared the Schiff base intermediate of 1 and 2a of model reaction in the presence of the CuO NPs catalyst separately and could be expected the formation of a copper complex of Schiff base (7). Aer that, the obtained complex intermediate was treated with 3a to get the nal product, 4a (Scheme 3). But, herein in addition to the expected product, 4a, (80%) an unexpected stereoisomer, 4a0 , (TLC) was also observed

Scheme 2

Schematic illustration of CuO NPs catalyzed synthesis of

4a–y.

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2

3 Possible schematic illustration of the synthesis of 4a & 4a0 via CuO NPs catalyzed Schiff base intermediate. Scheme 3

as a minor product (15%). It is concluding that the CuO NPs catalyst can act as a specic catalyst for alkynes. In summary, we have developed a novel and an efficient cascade reaction for the construction of highly functionalized phenyl-1H-pyrazolo[3,4-b]pyridine derivatives catalyzed by CuO NPs under mild reaction conditions. This methodology has the advantages of wide generality, high atom-economy efficiency, steric and functional group tolerance, high yields, short reaction times, environmental friendly protocol and reusability of the catalyst that keeps the catalyst efficiency aer four cycles even.

Experimental

4

5

6

General procedure for the synthesis of 6-(4-bromophenyl)-4(4-chlorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b] pyridine (4a) A mixture of 3-methyl-1-phenyl-1H-pyrazol-5-amine (1, 1.0 equiv.), 4-bromobenzaldehyde (2a, 1.0 equiv.) and 4-chloro-1ethynylbenzene (3a, 1.0 equiv.) are reacted in the presence of CuO NPs (10 mol%) in neat conditions at 80 C for 90 min. The completion of the reaction was monitored by TLC. The reaction mixture was cooled to room temperature followed by addition of ethyl acetate (10 mL) and ltered to recover the catalyst. Then the ltrate was denser under reduced pressure and obtained the solid product by washing with hexane and which was recrystallized from ethanol to afford the pure product. The precipitated CuO NPs was washed with methanol twice and then dried under vacuum before reuse.

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