Facile, novel and efficient synthesis of new pyrazolo[3,4-b]pyridine products from condensation of pyrazole-5-amine derivatives and activated carbonyl groups

Abstract

An efficient synthesis of novel ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate products has been achieved via condensation of pyrazole-5-amine derivatives and activated carbonyl groups, in refluxing acetic acid. This process has been found to be useful in the preparation of new N-fused heterocycle products in good to excellent yields.

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Introduction

N-fused heterocycles are one of the most important classes of organic compound with a multitude of applications and therefore there has been intense interest in the synthesis of this type of compound in recent decades.^1–3 They are widely present in naturally occurring alkaloids with a broad range of biological activities.⁴ Indeed, recent studies have shown that greater than 90% of molecules currently under analysis by pharmaceutical companies include nitrogen heterocycles, where pyrazol, pyridine and pyrimidine derivatives constitute the most important family of these compounds.⁵ In particular, fused pyridine systems such as pyrazolopyridines and their related derivatives have shown wide spectrums of biological activities for accessing the pharmaceutical and medicinal products.^6,7 For example, these heterocycles act as potent cyclin dependent kinase1 (CDK1) inhibitors,⁸ HIV reverse transcriptase inhibitors,⁹ CCR1 antagonists,¹⁰ protein kinase inhibitors,¹¹ inhibitors of cGMP degradation, dopamine D3 receptor antagonists, besides possessing antiherpetic and antiallergic,¹² herbicidal and fungicidal activities.¹³ Several drugs such as cartazolate, tracazolate and etazolate comprise pyrazolopyridine scaffold (Fig. 1).¹⁴

Fig. 1 Some drugs with pyrazolopyridine core.

There are several synthetic methods for preparation of these compounds under different conditions which has opened new horizons in the synthesis of pyrazolopyridines.¹⁵ For instance, the synthesis of pyrazolopyridines can be achieved via multi-component reaction of 1,3-diphenyl-1H-pyrazol-5-amine, barbituric acid and isatin,¹⁶ intermolecoular cyclization of 3-methyl-1-phenyl-1H-pyrazol-5-amine and bis(arylidene)thiophenones under microwave (MW) conditions,¹⁷ one-pot three-component condensation of kojic acid, 1H-pyrazol-5-amine and aldehydes,¹⁸ and four-component bicyclization of 2,2-dihydroxy-1-phenylethanone, 3-methyl-1-phenyl-1H-pyrazol-5-amine, aniline and 4-hydroxy-6-methyl-2H-pyran-2-one under microwave heating.¹⁹

These methods have one or more disadvantages such as adverse environmentally catalysts, toxic substances, low yields and wearing work up. Furthermore, these methods just provide a limited range of desired pyrazolo[3,4-b]pyridine structures. The biological and medicinal importance of these heterocyclics encourage us to search for a new and efficient method for their synthesis. In addition, we intend to introduce new pyrazolo[3,4-b]pyridine structures which are not available by previously presented strategies. Considering the above, herein we design a new, convenient, easy to handle, rapid and highly efficient protocol for the synthesis of novel analogues of pyrazolopyridines 3 via condensation reaction of pyrazol-5-amine compounds 1 and ethyl-2,4-dioxo-4-phenylbutanoate derivatives 2 under acidic conditions (Scheme 1). The target molecules were obtained in good to excellent isolated yields.

Scheme 1 General route for the synthesis of novel pyrazolo[3,4-b]pyridines.

Results and discussion

Initially, the desired starting materials, including 1,3-diphenyl-1H-pyrazol-5-amine 1 (R₁ = Ph; prepared from 1-phenyl hydrazine 6 and 3-oxo-3-phenylpropanenitrile 7), and ethyl-2,4-dioxo-4-arylbutanoates 2 (prepared from acetophenones 5 and diethyl oxalate 4) were synthesized by conventional methods according to the literature (Scheme 2).^20–22

Scheme 2 Synthesis of starting materials 1a (R₁ = Ph) and 2, needed for synthesis of pyrazolo[3,4-b]pyridine derivatives 3.

Next, the reaction of compound 1a (R₁ = Ph) and ethyl-2,4-dioxo-4-arylbutanoate 2a was studied comprehensively as a representative example. To access product 3a in a rapid and efficient manner, different solvents were examined (Table 1). As shown in Table 1, the expected product was obtained in good yield in refluxing AcOH (Table 1, entry 8). With these results in hand, different ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate derivatives 3a–q were prepared using various ethyl-2,4-dioxo-4-arylbutanoates 2 (Table 2, entries 1–17).

Table 1 Solvent screening for the synthesis of compound 3a

Entry	Solvent	Temperature	Time (h)	Yield^b (%)
a Catalytic amount (1 × 10^−4 mol%).b Isolated yield.
1	THF	68 °C	10	35
2	MeOH	65 °C	15	40
3	H2O	100 °C	12	42
4	H2O, HCl^a	100	8	38
5	H2O, CH3C6H4SO3H^a	100	9	40
6	H2O, AcOH^a	100	7	60
7	DMF	130 °C	13	38
8	AcOH	120 °C	5	90
9	HCl	100 °C	10	30

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Table 2 Synthesis of pyrazolo[3,4-b]pyridine-6-carboxylate derivatives 3

Entry	Ar-R2 on 2	Product 3	Yield^a (%)
a The reaction time was prolonged to 5 h.b The 1a was used as starting material.c The 1b was used as starting material.
1^b	Ph		90
2^b	4-F-C6H4		85
3^b	4-Br-C6H4		80
4^b	4-Cl-C6H4		82
5^b	2-Cl-C6H4		80
6^b	2,4-Cl2-C6H3		85
7^b	4-Me-C6H4		70
8^b	3-Me-C6H4		65
9^b	4-MeO-C6H4		60
10^b	3,4-(MeO)2-C6H3		65
11^b	3-MeO-C6H4		60
12^b	3,4,5-(MeO)3-C6H2		Trace
13^c	3-Me-C6H4		78
14^c	4-F-C6H4		87
15^c	4-MeO-C6H4		74
16^c	Ph		82
17^c	4-Br-C6H4		84

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It was observed that the desired products were obtained in good to excellent yields in almost all cases and their structures were confirmed by IR, ¹H NMR and ¹³C NMR spectroscopies as well as mass spectrometry.

A plausible mechanism for the formation of ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 3a is proposed in Scheme 3. The acid catalyzed condensation of primary amine group of 1,3-diphenyl-1H-pyrazol-5-amine 1a with the more active carbonyl group of ethyl-2,4-dioxo-4-phenylbutanoates 2a in the presence of acetic acid as solvent gave the intermediate 10. Finally, the products 3a can be achieved after tautomerization, cyclization and water elimination sequences. It should be noted that acetic acid can act as an efficient catalyst and suitable solvent for the synthesis of entitled fused pyrazolo[3,4-b]pyridine system.

Scheme 3 Plausible mechanism for the formation of ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate 3a.

Electron withdrawing groups on Ar of compound 2, draw electrons away from the neighboring carbonyl reaction center in intermediate 10, activate the carbonyl group and accelerate the cyclization step, which finally lead to higher yields of target products (Table 2, entries 2–6).

Meanwhile, the electron donating groups on Ar moiety of compound 2, decrease the nucleophilic attack to carbonyl group in intermediate 10, which lead to lower yields of desired products. In addition, the substitution effect on C-3 of compound 1, does not affect significantly the yield of the reaction (Table 2).

Experimental

Melting points were measured with a Kofler hot stage apparatus and are uncorrected. ¹H and ¹³C NMR spectra were recorded with a Bruker FT-500, using TMS as an internal standard. IR spectra were obtained with a Nicolet Magna FTIR 550 spectrophotometer (KBr disks). MS were recorded with an Agilent Technology (HP) mass spectrometer operating at an ionization potential of 70 eV. Elemental analysis was done by Elemental Analysensystem GmbH VarioEL CHNS mode.

General procedure for the synthesis of pyrazolo[3,4-b]pyridine-6-carboxylate (3)

At the outset, a mixture of 1,3-diphenyl-1H-pyrazol-5-amine 1 (1 mmol) and ethyl-2,4-dioxo-4-arylbutanoates 2 (1 mmol) in refluxing CH₃CO₂H (10 mL) was stirred for 5 h. The progress of the reaction was monitored by TLC (ethyl acetate/n-hexane: 1/2). After completion of the reaction, it was cooled to room temperature, and the precipitated product was filtered, washed with ethanol (20 mL) and purified by crystallization or column chromatography to afford the pure product 3a–k as a pure powder.

Ethyl-1,3,4-triphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3a). Yield: 90%; yellow crystals; mp 114–116 °C; IR (KBr): 3063, 2983, 1722, 1596 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ = 0.82 (t, J = 7.1 Hz, 3H, CH₃), 3.96 (q, J = 7.1 Hz, 2H, OCH₂), 7.37 (t, J = 7.3 Hz, 1H, Ar), 7.47–7.61 (m, 8H, Ar), 7.68 (d, J = 7 Hz, 2H, Ar), 8.06 (s, 1H, pyridine), 8.23 (d, J = 7.4 Hz, 2H, Ar), 8.44 (d, J = 8.1 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 62.0, 110.2, 115.1, 121.6, 126.2, 127.5, 128.2, 128.4, 128.6, 128.9, 129.0, 130.0, 134.0, 135.5, 138.1, 139.3, 145.4, 151.8, 157.0, 166.6. MS: m/z (%) = 419 [M]⁺ (100), 346 (50), 265 (30), 117 (25), 77 (15). Anal. calcd for C₂₇H₂₁N₃O₂: C, 77.31; H, 5.05; N, 10.02; found: C, 76.91; H, 4.65; N, 9.62.

Ethyl-4-(4-fluorophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3b). Yield: 85%; yellow crystals; mp 151 °C; IR (KBr): 3062, 2979, 1724, 1499 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.80 (t, J = 7.5 Hz, 3H, CH₃), 3.94 (q, J = 7.5 Hz, 2H, OCH₂), 7.20–7.25 (m, 2H, Ar), 7.35–7.38 (m, 1H, Ar), 7.46–7.52 (m, 3H, Ar), 7.55–7.59 (m, 2H, Ar), 7.64–7.66 (m, 2H, Ar), 7.98 (s, 1H, pyridine), 8.19–8.22 (m, 2H, Ar), 8.38–8.40 (m, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 62.1, 110.2, 114.8, 115.9 (d, J_C–F = 21.2 Hz), 121.7, 126.3, 128.3, 128.5, 128.6, 129.0, 129.5 (d, J_C–F = 8.7 Hz), 133.9, 134.3, 135.7, 139.2, 145.4, 151.7, 156.0 (d, J_C–F = 250 Hz), 164.1, 166.5. MS: m/z (%) = 424 [M]⁺ (100), 418 (45), 346 (30), 77 (25). Anal. calcd for C₂₇H₂₀FN₃O₂: C, 74.13; H, 4.61; N, 9.61; found: C, 73.73; H, 4.21; N, 9.21.

Ethyl-4-(4-bromophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3c). Yield: 80%; yellow crystals; mp 186 °C; IR (KBr): 3062, 2986, 1724, 1574 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.85 (t, J = 7.1 Hz, 3H, CH₃), 3.99 (q, J = 7.1 Hz, 2H, OCH₂), 7.04 (t, J = 7,1 Hz, 1H, Ar), 7.50–7.54 (m, 3H, Ar), 7.59–7.62 (m, 2H, Ar), 7.68–7.72 (m, 4H, Ar), 8.03 (s, 1H, pyridine), 8.12 (d, J = 8.5 Hz, 2H, Ar), 8.43 (d, J = 7.7 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.6, 62.5, 110.2, 115.2, 121.5, 126.2, 127.5, 128.2, 128.4, 128.6, 128.9, 129, 130.0, 134.0, 135.5, 138.1, 139.3, 145.5, 151.8, 157.0, 166.6. MS: m/z (%) = 497 [M⁺] (100), 470 (30), 242 (25), 77 (35). Anal. calcd for C₂₇H₂₀BrN₃O₂: C, 65.07; H, 4.04; N, 8.43. Found: C, 64.67; H, 3.64; N, 8.04.

Ethyl-4-(4-chlorophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3d). Yield: 80%; yellow crystals; mp 186 °C; IR (KBr): 3060, 2987, 1723, 1565 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.85 (t, J = 7.1 Hz, 3H, CH₃), 3.98 (q, J = 7.1 Hz, 2H, OCH₂), 7.40 (t, J = 7 Hz, 1H, Ar), 7.50–7.56 (m, 5H, Ar), 7.59–7.62 (m, 2H, Ar), 7.68–7.70 (m, 2H, Ar), 8.03 (s, 1H, pyridine), 8.19 (dd, J = 6.7, 1.8 Hz, 2H, Ar), 8.4 (dd, J = 8, 0.90 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.6, 62.5, 110.2, 115.2, 122.1, 128.7, 128.9, 129.1, 129.2, 129.3, 129.5, 129.6, 130.0, 134.0, 135.1, 138.7, 139.6, 145.4, 151.5, 157.4, 166.6. MS: m/z (%) = 453 [M⁺] (100), 418 (40), 346 (35), 77 (30). Anal. calcd for C₂₇H₂₀ClN₃O₂: C, 71.44; H, 4.44; N, 9.26. Found: C, 71.04; H, 4.04; N, 8.86.

Ethyl-4-(2-chlorophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3e). Yield: 80%; yellow crystals; mp 190 °C; IR (KBr): 3062, 2975, 1731, 1595 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.83 (t, J = 7.2 Hz, 3H, CH₃), 3.97 (q, J = 7.2 Hz, 2H, OCH₂), 7.34 (t, J = 7.2 Hz, 1H, Ar), 7.42–7.45 (m, 2H, Ar), 7.51–7.56 (m, 6H, Ar), 7.68–7.75 (m, 3H, Ar), 7.92 (s, 1H, pyridine), 8.4 (d, J = 7.8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 62.1, 118.7, 119.1, 119.6, 121.5, 121.9, 126.3, 127.2, 128.6, 128.9, 129.2, 129.5, 130.3, 130.6, 132.1, 132.6, 133.9, 134.8, 138.3, 139.1, 156.7, 166.3. MS: m/z (%) = 435 [M⁺] (100), 418 (40), 346 (30), 77 (15). Anal. calcd for C₂₇H₂₀ClN₃O₂: C, 70.40; H, 5.46; N, 7.68. Found: C, 70.0; H, 5.02; N, 7.28.

Ethyl-4-(2,4-dichlorophenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3f). Yield: 85%; yellow crystals; mp 135 °C; IR (KBr): 2982, 2929, 1719, 1592 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.82 (t, J = 7.1 Hz, 3H, CH₃), 3.96 (q, J = 7.1 Hz, 2H, OCH₂), 7.49–7.50 (m, 1H, Ar), 7.51–7.53 (m, 1H, Ar), 7.56–7.58 (m, 6H, Ar), 7.66–7.69 (m, 3H, Ar), 7.89 (s, 1H, pyridine), 8.35–8.38 (m, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 62.1, 110.4, 118.8, 121.6, 126.4, 127.5, 128.3, 128.6, 128.7, 129.0, 130.2, 132.8, 133.3, 133.8, 134.9, 135.6, 136.7, 139.0, 145.4, 151.3, 155.5, 166.1. Anal. calcd for C₂₇H₂₀Cl₂N₃O₂: C, 66.40; H, 3.92; N, 8.60. Found: C, 66.0; H, 3.52; N, 8.20.

Ethyl-1,3-diphenyl-4-p-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3g). Yield: 70%; yellow crystals; mp 164 °C; IR (KBr): 2982, 2929, 1729, 1493, 1462 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.84 (t, J = 7.1 Hz, 3H, CH₃), 2.48 (s, 3H, CH₃), 3.98 (q, J = 7.1 Hz, 2H, OCH₂), 7.39 (t, J = 8.1 Hz, 3H, Ar), 7.49–7.55 (m, 3H, Ar), 7.60 (t, J = 8.2 Hz, 2H, Ar), 7.69–7.70 (m, 2H, Ar), 8–05 (s, 1H, pyridine), 8.15 (d, J = 8.1 Hz, 2H, Ar), 8.47 (d, J = 7.7 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 22.0, 62.3, 110.2, 115.2, 122.1, 128.7, 128.9, 129.1, 129.2, 129.3, 129.5, 129.6, 130.0, 134.0, 135.0, 138.7, 139.6, 145.4, 151.8, 157.0, 166.0. Anal. calcd for C₂₈H₂₃N₃O₂: C, 77.58; H, 5.35; N, 9.69. Found: C, 77.18; H, 4.95; N, 9.29.

Ethyl-1,3-diphenyl-4-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3h). Yield: 70%; yellow crystals; mp 141 °C; IR (KBr): 3035, 2974, 2919, 1720 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.85 (t, J = 7.1 Hz, 3H, CH₃), 2.52 (s, 3H, CH₃), 3.98 (q, J = 7.1 Hz, 2H, OCH₂), 7.29 (s, 1H, Ar), 7.35 (s, 1H, Ar), 7.39 (s, 1H, Ar), 7.47–7.51 (m, 1H, Ar), 7.54–7.55 (m, 2H, Ar), 7.59–7.62 (m, 2H, Ar), 7.69–7.71 (m, 2H, Ar), 8.03 (d, J = 7 Hz, 2H, Ar), 8.07 (s, 1H, pyridine), 8.48 (d, J = 7.6 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): δ_c = 13.17, 24.7, 60.08, 109.2, 115.2, 115.7, 121.5, 121.8, 126.1, 128.5, 128.8, 129.1, 129.8, 130.7, 132.7, 134.0, 135.5, 139.3, 139.6, 145.4, 151.9, 156.8, 160.1, 166.6. Anal. calcd for C₂₈H₂₃N₃O₂: C, 77.58; H, 5.35; N, 9.69. Found: C, 77.18; H, 4.95; N, 9.29.

Ethyl-4-(4-methoxyphenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3i). Yield: 60%; yellow crystals; mp 169 °C; IR (KBr): 3061, 2962, 2928, 1732, 1571 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.08 (t, J = 7.1 Hz, 3H, CH₃), 3.91 (s, 3H, OCH₃), 3.95 (q, J = 7.1 Hz, 2H, OCH₂), 7.06 (d, J = 8.8 Hz, 2H), 7.25 (t, J = 7 Hz, 1H, Ar), 7.48–7.51 (m, 3H, Ar), 7.55–7.60 (m, 2H, Ar), 7.65–7.68 (m, 2H, Ar), 7.99 (s, 1H, pyridine), 8.19 (d, J = 8.8 Hz, 2H, Ar), 8.43 (dd, J = 8.5, 1.1 Hz, 2H, Ar), ¹³C NMR (125 MHz, CDCl₃): 13.1, 55.4, 61.9, 109.7, 110.2, 114.3, 114.5, 121.6, 126.1, 128.2, 128.4, 128.6, 129.0, 130.7, 134.1, 135.3, 139.3, 145.4, 151.9, 156.7, 161.3, 166.7. MS: m/z (%) = 449.5 [M⁺] (100), 419 (40), 342 (30), 77 (25). Anal. calcd for C₂₈H₂₃N₃O₃: C, 74.82; H, 5.16; N, 9.35. Found: C, 74.42; H, 4.76; N, 8.95.

Ethyl-4-(3,4-dimethoxyphenyl)-1,3-diphenyl-1-pyrazolo[3,4-b]pyridine-6-carboxylate (3j). Yield: 65%; yellow crystals; mp 109 °C; IR (KBr): 2923, 2851, 1722, 1571 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.80 (t, J = 7.1 Hz, 3H, CH₃), 3.93 (q, J = 7.1 Hz, 2H, OCH₂), 3.98 (s, 3H, OCH₃), 4.04 (s, 3H, OCH₃), 7.02 (d, J = 8.4 Hz, 1H, Ar), 7.26–7.35 (m, 1H, Ar), 7.49–7.58 (m, 5H, Ar), 7.56–7.68 (m, 2H, Ar), 7.78–7.81 (m, 1H, Ar), 7.87 (d, J = 1.8 Hz, 1H, Ar), 8.0 (s, 1H, pyridine), 8.44 (d, J = 7.8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 55.9, 56.0, 62.0, 109.8, 110.2, 111.1, 114.5, 120.5, 121.6, 126.1, 128.3, 128.4, 128.6, 128.9, 130.9, 134.0, 135.4, 139.3, 145.4, 149.3, 150.9, 156.5, 166.8. MS: m/z (%) = 479 [M⁺] (100), 418 (60), 342 (35), 77 (25). Anal. calcd for C₂₉H₂₅N₃O₄: C, 72.64; H, 5.25; N, 8.76. Found: C, 72.24; H, 4.75; N, 8.36.

Ethyl-4-(3-methoxyphenyl)-1,3-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3k). Yield: 60%; yellow crystals; mp 139 °C; IR (KBr): 2922, 2853, 1721, 1572 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 0.82 (t, J = 7.2 Hz, 3H, CH₃), 3.94 (s, 3H, OCH₃), 4.00 (q, J = 7.5 Hz, OCH₂), 7.06 (d, J = 7.5 Hz, 1H, Ar), 7.37 (t, J = 7.5 Hz, 1H, Ar), 7.39–7.61 (m, 6H, Ar), 7.68 (d, J = 6.6 Hz, 2H, Ar), 7.80 (d, J = 7.2 Hz, 2H, Ar), 8.04 (s, 1H, pyridine), 8.45 (d, J = 8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 13.1, 55.9, 62.0, 109.2, 115.2, 115.7, 121.5, 121.8, 126.1, 128.5, 128.8, 129.1, 129.8, 130.0, 132.7, 134.0, 135.5, 139.3, 139.6, 151.8, 156.8, 157.1, 160.1, 166.6. Anal. calcd for C₂₈H₂₃N₃O₃: C, 74.82; H, 5.16; N, 9.35. Found: C, 74.42; H, 4.76; N, 8.95.

Ethyl-3-methyl-1-phenyl-4-m-tolyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3m). Yield: 78%; yellow crystals; mp 128–130 °C; IR (KBr): 2912, 2853, 1721, 1562 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 1.5 (t, J = 7 Hz, 3H, CH₃), 2.47 (s, 3H, CH₃), 2.79 (s, 3H, CH₃), 4.54 (q, J = 7 Hz, OCH₂), 7.27–7.31 (m, 2H, Ar), 7.40 (t, J = 7.5 Hz, 1H, Ar), 7.53 (t, J = 7.5 Hz, 2H, Ar), 7.97 (d, J = 8 Hz, 2H, Ar), 8.09 (s, 1H, pyridine), 8.35 (d, J = 8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 14.30, 16.28, 21.59, 62.03, 111.96, 115.25, 121.32, 124.77, 125.68, 128.18, 128.81, 128.94, 130.62, 134.24, 138.40, 138.50, 139.47, 142.51, 152.16, 156.87, 165.72. Anal. calcd for C₂₃H₂₁N₃O₂: C, 74.37; H, 5.70; N, 11.31. Found: C, 74.44; H, 5.77; N, 11.62.

Ethyl-4-(4-fluorophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3n). Yield: 87%; yellow crystals; mp 132 °C, IR (KBr): 2942, 2753, 1731, 1562 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 1.50 (t, J = 7 Hz, 3H, CH₃), 2.78 (s, 3H, CH₃), 4.53 (q, J = 7 Hz, 2H, OCH₂), 7.19 (t, J = 8 Hz, 2H, Ar), 7.30 (t, J = 7.5 Hz, 1H, Ar), 7.53 (t, J = 8 Hz, 2H, Ar), 8.04 (s, 1H, pyridine), 8.15 (d, J = 8 Hz, 2H, Ar), 8.30 (d, J = 8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 14.29, 16.30, 62.01, 111.95, 114.74, 115.87 (d_C–F, J = 21.25 Hz), 121.32, 125.79, 128.97, 129.4 (d_C–F, J = 8.75 Hz), 134.41, 134.50, 139.35, 142.57, 152.04, 155.50, 163.07, 165.0 (d_C–F, J = 240 Hz). Anal. calcd for C₂₂H₁₈FN₃O₂: C, 70.39; H, 4.83; N, 11.19. Found: C, 70.52; H, 4.74; N, 11.27.

Ethyl-4-(4-methoxyphenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3o). Yield: 74%; yellow crystals; mp 131–132 °C, IR (KBr): 2922, 2973, 1721, 1512 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): 1.50 (t, J = 7 Hz, 3H, CH₃), 2.78 (s, CH₃), 3.88 (s, OCH₃), 4.53 (q, J = 7 Hz, 2H, OCH₂), 7.02–7.05 (m, 2H, Ar), 7.28–7.31 (m, 1H, Ar), 7.51–7.54 (m, 2H, Ar), 8.06 (s, 1H, pyridine), 8.13–8.16 (m, 2H, Ar), 8.33–8.35 (m, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 14.30, 16.30, 55.42, 62.01, 111.5, 114.33, 114.60, 121.31, 125.63, 128.94, 130.98, 134.20, 139.50, 142.54, 144.30, 152.20, 156.36, 161.27, 165.79. Anal. calcd for C₂₃H₂₁N₃O₃: C, 71.30; H, 5.46; N, 10.85. Found: C, 71.45; H, 5.64; N, 10.72.

Ethyl-3-methyl-1,4-diphenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3p). Yield: 82%; yellow crystals; mp 128–129 °C; IR (KBr): 2902, 2753, 1721, 1562 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): δ_H = 1.49 (t, J = 7 Hz, 3H, CH₃), 2.78 (s, CH₃), 4.52 (q, J = 7 Hz, OCH₂), 7.29 (t, J = 7 Hz, 1H, Ar), 7.45–7.53 (m, Ar, 5H), 8.09 (s, pyridine), 8.16 (d, J = 8 Hz, 2H, Ar), 8.34 (d, J = 8 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 14.26, 16.29, 62.02, 112.00, 115.10, 121.26, 125.67, 127.50, 128.86, 128.92, 129.80, 134.25, 138.33, 139.40, 142.51, 152.11, 156.58, 165.60. Anal. calcd for C₂₂H₁₉N₃O₂: C, 73.93; H, 5.36; N, 11.76. Found: C, 74.15; H, 5.52; N, 11.98.

Ethyl-4-(4-bromophenyl)-3-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-6-carboxylate (3q). Yield: 84%; yellow crystals; mp 141–142 °C, IR (KBr): 2942, 2773, 1701, 1522 cm⁻¹. ¹H NMR (500 MHz, CDCl₃): 1.50 (t, J = 7 Hz, 3H, CH₃), 2.80 (s, CH₃), 4.54 (q, J = 7 Hz, 2H, OCH₂), 7.31 (t, J = 7.5 Hz, 1H, Ar), 7.53 (t, J = 7.5 Hz, 2H, Ar), 7.65 (d, J = 8.5 Hz, 2H, Ar), 8.05 (d, J = 8.5 Hz, 2H, Ar), 8.07 (s, 1H, pyridine), 8.30 (d, J = 8.5 Hz, 2H, Ar). ¹³C NMR (125 MHz, CDCl₃): 14.30, 16.28, 62.16, 112.90, 114.77, 119.90, 121.39, 124.50, 124.90, 125.89, 129.01, 129.05, 132.12, 134.1, 137.4, 139.2, 142.6, 155.3. Anal. calcd for C₂₂H₁₈BrN₃O₂: C, 60.56; H, 4.16; N, 9.63. Found: C, 60.78; H, 4.35; N, 9.86.

Conclusions

In conclusion, we have introduced a simple, innovative and efficient route for the synthesis of new pyrazolo[3,4-b]pyridine-6-carboxylates 3 using readily available starting materials. Advantages such as the absence of complex synthetic catalyst, relatively short reaction times, high yields of the products, operational simplicity, easy work-up procedure and no requirement for time-consuming purification steps can make the method useful for chemists interested in developing novel pyrazolopyridine-based drugs. Furthermore, our strategy expands the scope of available pyrazolo[3,4-b]pyridine fused heterocycles which can not be prepared by previously reported methods.

Acknowledgements

This research was supported by grants from PNU, the research council of Tehran University of Medical Sciences and Iran National Science Foundation (INSF).

Notes and references

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/c5ra16769h

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