English

• 1.   Introduction

  From the economical point of view and simplicity, multicomponent reactions (MCRs) offer significant advantages over conventional linear-type synthesis. MCRs are powerful synthetic tools for the construction of a complex target compound with attractive biological properties from simple starting materials via one-pot procedure without complex purification. These reactions comply with principles of green chemistry and ensure atomic economy, high yield and selectivity, minimize waste, save labor and manpower, reduce time consumption, solvents and raw materials.^[1~11]

  The development of new and green approaches toward the synthesis of biologically active polyheterocyclic scaffolds has attracted significant interest due to the importance of these compounds to drug discovery.^[12~14] The pyrazolo[3, 4-b]pyridine compounds contain two major components, pyrazole and pyridine, have been found numerous applications in medical chemistry, agrochemicals and functional materials.^[15~19] Heterocycles containing the pyrazole unit are important targets in synthetic and medicinal chemistry because they are the key moieties in numerous biologically active compounds.^[14] Pyridine is one of the most privileged members of the heterocyclic family, and its derivatives exhibit a wide range of applications in the areas of pharmaceuticals, pesticides, and chemical materials.^[20~23] In addition, the carbonitrile group is also useful functional group and exhibits some applications in various synthetic transformations especially as a synthetic precursor to access amide and amine though the well-known Hofmann-style rearrangement.^[7] Accordingly, the synthetic methods for the pyrazolo[3, 4-b]pyridine core have been reported, relying on condensation reactions of either 1, 3-dicarbonyl or α, β-unsaturated carbonyl compounds with 5-aminopyrazoles, ^[24] or on the cyclization of hydrazines with appropriately substituted derivatives of nicotinic acid.^{[25, 26]} Recently, Aggarwal et al.^[27] reported an efficient method for synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]-pyridine-5-nitriles by the condensation of 3-aryl-3-oxopro-panonitriles and mono-substituted aryl/heteroarylhydra-zines in ethanol in the presence of conc. HNO₃. 4, 7-Di-hydro-1H-pyrazolo[3, 4-b]pyridine-5-nitriles can be easily converted to 1H-pyrazolo-[3, 4-b]pyridine-5-nitriles with sodium nitrite in acetic acid at ambient temperature.^[28]

  Recently, deep eutectic solvents (DESs) as a new generation solvent have attracted enormous attention.^[29] They are generally formed by the mixing a solid organic salt or molecule (hydrogen bond acceptor, HBA) with a hydrogen bond donor (HBD) in suitable molar ratios leading to a eutectic mixture with reduced melting point that is close to ambient temperature. DESs have similar characteristics as ionic liquids (ILs) but are less toxic, better biodegradable, and easier preparation, enabling them potential to replace volatile organic solvents and ILs in many fields such as CO₂ capture, ^[30] fuel desulfurization, ^[31] biodiesel production, ^[32] polymer synthesis, ^[33] biochemistry, ^[34] functional materials, ^[35] and separation.^[36] Especially, DESs have been also gained wide recognition to act as solvent or catalyst in the development of environmentally friendly organic reactions.^[37~45] Thus, the combination of MCRs and DESs should make the organic reaction easier, reduce the number of separation steps, and effectively utilize all the reactants within the product's framework.

  Against this background and in continuation of our interest toward the development of new efficient synthetic methodologies for the construction of hetero-cycles, ^[46~54] herein, we wish to report a novel, DES-catalyzed method for the synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyri-dine-5-carbonitrile derivatives via one-pot, three-compo-nent reaction of aldehyde, 3-oxopropanenitrile and 1H-pyrazol-5-amine (Scheme 1).

  Scheme 1

  

  Scheme 1.  Proline/oxalic acid catalyzed synthesis of 4, 7-dihy-dro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives

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  2.   Results and discussion

  For our initial investigation, three-component reaction of benzaldehyde, 3-oxo-3-phenylpropanenitrile and 1, 3-di-phenyl-1H-pyrazol-5-amine was selected as a model reaction to optimize reaction conditions. As shown in Table 1, almost no desired product was obtained in the absence of a catalyst when the reaction mixture was heated at 100 ℃ under solvent-free conditions (Table 1, Entry 1). The yields could be improved when the reaction was performed in refluxing tetrahydrofuran (THF), dimethylformamide (DMF), MeOH or EtOH. In order to make the reaction more efficient, the model reaction was carried out in the presence of various catalysts including FeCl₃, NH₂SO₃H, CH₃SO₃H, p-toluenesulfonic acid (p-TSA), CH₃COOH, L-lysine, oxalic acid, L-proline and proline/oxalic acid. It was found that deep eutectic solvent based on L-proline and oxalic acid gave the best yield (Table 1, Entry 15). Then, the effect of different temperature on the model reaction using L-proline/ oxalic acid as the catalyst was investigated. It was observed that low temperature resulted in lower product yields (Entries 16~18). In addition, it was found that the catalyst loading affected the model reaction. The yield decreased using 10 mol% catalyst, while there was no significant variation in the product yield upon increasing the catalyst amount to 30 mol% (Entries 19, 20). From these observations, we concluded that 20 mol% L-proline/oxalic acid in refluxing EtOH are the optimized reaction condition for the synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives.

  Table 1

  

  Table 1.  Reaction of benzaldehyde, 3-oxo-3-phenylpropanenitrile and 1, 3-diphenyl-1H-pyrazol-5-amine under different conditions^a

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  Entry	Catalyst	Solvent	Temp./℃	Time/h	Yieldb/%
  1	No	No	100	8.0	Trace
  2	No	H2O	Reflux	8.0	Trace
  3	No	THF	Reflux	8.0	13
  4	No	DMF	Reflux	8.0	25
  5	No	MeOH	Reflux	8.0	54
  6	No	EtOH	Reflux	8.0	58
  7	FeCl3	EtOH	Reflux	4.0	79
  8	NH2SO3H	EtOH	Reflux	4.0	80
  9	CH3SO3H	EtOH	Reflux	4.0	82
  10	p-TSA	EtOH	Reflux	4.0	83
  11	CH3COOH	EtOH	Reflux	4.0	85
  12	L-Lysine	EtOH	Reflux	4.0	84
  13	Oxalic acid	EtOH	Reflux	4.0	81
  14	L-Proline	EtOH	Reflux	4.0	86
  15	L-Proline/oxalic acid	EtOH	Reflux	4.0	92
  16	L-Proline/oxalic acid	EtOH	r.t.	4.0	24
  17	L-Proline/oxalic acid	EtOH	40	4.0	56
  18	L-Proline/oxalic acid	EtOH	60	4.0	73
  19c	L-Proline /oxalic acid	EtOH	Reflux	4.0	89
  20d	L-Proline/oxalic acid	EtOH	Reflux	4.0	92
  21e	L-Proline/oxalic acid	EtOH	Reflux	4.0	93
  22f	L-Proline/oxalic acid	EtOH	Reflux	4.0	92, 91, 91, 90, 89
  a Reaction conditions: benzaldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile (1 mmol) and 1, 3-diphenyl-1H-pyrazol-5-amine (1 mmol), catalyst (20 mol%) in solvent (2 mL) otherwise specified in the table. b Isolated yields. c 10 mol% catalyst was used. d 30 mol% catalyst was used. e The reaction was carried out in 10 mmol scale. f Catalyst was reused for five times.

  To demonstrate the synthetic potential of this method, the model reaction was enlarged to gram-scale. For example, when the reaction of aldehyde, 3-oxopropanenitrile and 1H-pyrazol-5-amine was processed on 10 mmol scale, the product 4a was obtained in 93% yield after workup (Entry 21). On the same scale, the recovery and recyclability of DES were also investigated for the above model reaction. After completion of the reaction, the mixture was cooled to room temperature and water was added to the reaction mixture. The resulted insoluble solid product was separated by simple filtration and washed with water. The filtrate was evaporated under reduced pressure and the recovered DES could be reused in subsequent runs under similar experimental conditions. To our delight, it was found that recovered DES can be reused fifth cycle in the model reaction without loss of activity (Table 1, Entry 22). These results demonstrated the high stability of the catalyst under experimental conditions.

  Having established the optimal reaction conditions, the generality and scope of this protocol were explored. As revealed in Table 2, the results indicated that aromic aldehydes bearing electron-donating and electron-with-drawing substituents at different position in the benzene ring were all compatible with this reaction. A series of funtional groups, such as methoxy, ethoxy, hydroxyl, halogen, cyano, and trifluoromethyl, were well-tolerated and give the corresponding products in high to excellent yields. It was noticed that nature of the substituents shows no significant influence on the reaction times and the yields of the products. Impressively, heteroaromatic aldehydes with furanyl, thienyl and pyridyl groups were also tolerated under reaction conditions, but leading to the expected products in relatively low yields (Table 2, Entries 18~20). This protocol was successfully applied to aliphatic aldehyde such as cyclohexanecarbaldehyde, delivering product 4uin 75% yield (Entry 21). Pleasingly, 3-phenylpropiolaldehyde is also an approprite substrate which afforded the goal product 4v in 82% yield (Entry 22).

  Table 2

  

  Table 2.  Synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives catalyzed by oxalic acid/proline^a

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  Entry	Aldehyde	X	Product	Time/h	Yieldb/%
  1	PhCHO	CH	4a	1.0	95
  2	2-MeOC6H4CHO	CH	4b	1.0	90
  3	3-MeOC6H4CHO	CH	4c	1.0	94
  4	4-MeOC6H4CHO	CH	4d	1.0	93
  5	3, 4-(MeO)2C6H3CHO	CH	4e	1.5	90
  6	2, 3, 4-(MeO)3C6H2CHO	CH	4f	1.5	82
  7	3, 4, 5-(MeO)3C6H2CHO	CH	4g	1.5	85
  8	4-EtOC6H4CHO	CH	4h	1.0	91
  9	4-HO-C6H4CHO	CH	4i	1.0	91
  10	4-MeC6H4CHO	CH	4j	1.0	92
  11	4-Me3CC6H4CHO	CH	4k	1.0	90
  12	4-ClC6H4CHO	CH	4l	1.0	90
  13	2-BrC6H4CHO	CH	4m	1.0	90
  14	3-BrC6H4CHO	CH	4n	1.0	92
  15	4-BrC6H4CHO	CH	4o	1.0	95
  16	4-O2NC6H4CHO	CH	4p	1.0	87
  17	4-NCC6H4CHO	CH	4q	1.0	88
  18	Furan-2-carbaldehyde	CH	4r	2.0	72
  19	Thiophene-2-carbaldehyde	CH	4s	2.0	76
  20	4-Pyridine-carbaldehyde	CH	4t	2.0	79
  21	Cyclohexanecarbaldehyde	CH	4u	3.0	75
  22	3-Phenylpropiolaldehyde	CH	4v	2.0	82
  23	PhCHO	N	4w	1.5	90
  24	4-MeC6H4CHO	N	4x	1.5	91
  25	4-O2NC6H4CHO	N	4y	1.5	93
  a Reaction conditions: aldehyde (1 mmol), 3-oxopropanenitrile (1 mmol), 1H-pyrazol-5-amine (1 mmol) and oxalic acid/proline (0.2 mmol) in refluxing EtOH (2 mL). b Isolated yield.

  In view of these results, we turned our attention to investigate different 3-oxopropanenitrile. To our delight, when 3-oxo-3-(pyridin-3-yl)propanenitrile was employed instead of 3-oxo-3-phenylpropanenitrile, the reactions were carried out smoothly and the desired products were obtained in high yields (Entries 23~25).

  Successively, the scope of this reaction was extended to a substrate containing two aldehyde groups such as terephthalaldehyde and [1, 1'-biphenyl]-4, 4'-dicarbaldehyde. As shown in Scheme 2, treatment of terephthalaldehyde or [1, 1'-biphenyl]-4, 4'-dicarbaldehyde (1 mmol) with 3-oxo-3-phenyl-propanenitrile (1 mmol) and 1, 3-diphenyl-1H-py-razol-5-amine (1 mmol) under above optimal conditions led to formation of the corresponding products 5a and 5b in 89% and 88% yield, respectively.

  Scheme 2

  

  Scheme 2.  Synthesis of bis(4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile) derivatives

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  To our surprise, when dialkyl-substituted pyrazolamine such as 1, 3-dimethyl-1H-pyrazol-5-amine was utilized as the substrate under above condition, dehydrative product 6 was formed in 68% yield (Scheme 3). Sadly, it was found that aliphatic ketone acetonitrile such as 4, 4-dimethyl-3-oxopentanenitrile is not a suitable substrate, resulting in an inseparable mixture.

  Scheme 3

  

  Scheme 3.  Synthesis of 1, 3-dimethyl-4, 6-diphenyl-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile

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  On the basis of the experimental results, a plausible reaction mechanism for the formation of 1, 3, 4, 6-tetraphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4a) was proposed (Scheme 4). In the presence of DES, benzaldehyde (1) and 3-oxo-3-phenylpropanenitrile (2) were activated. An acrylonitrile intermediate Ⅰ was formed by the Knoevenagel condensation between activated aldehyde and the enol form of 2. Then, a Michael addition of 1, 3-di-phenyl-1H-pyrazol-5-amine (3) to the C＝C bond of intermediate Ⅰ occurred in the presence of the DES, resulting in the adduct Ⅱ. Successively, an intramolecular cyclic condensation between the amino and the carbonyl groups of the Michael adduct Ⅱ took place to yield intermediate Ⅲ, which finally underwent dehydration to afford the desired product 4a. We think that the hydrogen bonding nature of DES facilitates the electrophilic activation of the carbonyl groups in three steps: Knoevenagel condensation, Michael addition and intramolecular cyclization.

  Scheme 4

  

  Scheme 4.  Plausible reaction mechanism

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  3.   Conclusions

  In conclusion, a novel, simple and versatile route has been developed for the synthesis of 4, 7-dihydro-1H-pyra-zolo[3, 4-b]pyridine-5-carbonitrile derivatives through one-pot three-component reaction of aldehyde, 3-oxopropane-nitrile and 1H-pyrazol-5-amine. A wide of aldehydes and 3-oxopropanenitrile can be tolerated, giving the structural diversity of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives in good to excellent yields. Morever, the catalyst can be successfully recovered and reused for five times with no significant loss of its catalytic performance.

  4.   Experimental

  4.1   General information

  All the chemicals and solvents are commercially available and were used as received without further purification. Oxalic acid/L-proline was prepared according to the reported method in the literature.^[55] Melting points were obtained on an X-5 digital melting point apparatus and uncorrected. The FT-IR spectra were recorded using a Bruker Tensor 27 spectrometer. ¹H NMR (500 MHz) and ¹³C NMR (125 MHz) spectra of the products were obtained using a Bruker DRX-500 spectrometer with DMSO-d₆ as solvent. High resolution mass spectra (HRMS) were performed on a Q-TOF spectrometer.

  4.2   General procedure for synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives

  To a solution of aldehyde (1 mmol), 3-oxopropaneni-trile (1 mmol), 1H-pyrazol-5-amine (1 mmol) in ethanol (2 mL), oxalic acid/proline (0.2 mmol) was added, and the reaction mixture was heated to reflux [monitored by thin layer chromatography (TLC)]. After completion of the reaction, the reaction mixture was cooled to room temperature and cold water (5 mL) was added. The precipitate was collected, washed with a little cold water and recrystallized from ethanol to give the pure product. The DES could be recovered by evaporating the water and ethanol under reduced pressure. The recovered DES could be reused in subsequent runs.

  1, 3, 4, 6-Tetraphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]py-ridine-5-carbonitrile (4a): White powder; m.p. 103~104 ℃; ¹H NMR (500 MHz, DMSO-d₆)δ: 9.99 (s, 1H), 7.68 (d, J＝7.0 Hz, 2H), 7.57~7.51 (m, 6H), 7.48~7.38 (m, 4H), 7.25~7.18 (m, 7H), 7.15~7.12 (m, 1H), 5.37 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 149.7, 147.6, 145.6, 138.8, 138.6, 134.4, 133.1, 130.7, 129.9, 129.8, 129.7, 129.3, 129.0, 128.7, 128.2, 127.9, 127.4, 127.2, 124.4, 122.3, 100.2, 85.6; IR (KBr) ν: 3431, 2988, 2199, 1625, 1541, 1277, 1045, 762, 696 cm^－1; HRMS (ESI) calcd for C₃₁H₂₃N₄ (M+H)⁺ 451.1923, found 451.1920.

  4-(2-Methoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4b): White powder; m.p. 110~111 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.89 (s, 1H), 7.68 (d, J＝7.0 Hz, 2H), 7.58 (d, J＝7.0 Hz, 2H), 7.55~7.50 (m, 6H), 7.46~7.37 (m, 4H), 7. 25~7.19 (m, 3H), 7.15~7.09 (m, 2H), 6.94 (d, J＝8.5 Hz, 1H), 6.84 (t, J＝7.0 Hz, 1H), 5.69 (s, 1H), 3.80 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 151.1, 144.8, 141.9, 134.1, 133.4, 129.3, 128.5, 127.9, 125.3, 124.5, 124.1, 123.6, 123.3, 122.9, 122.6, 121.7, 119.0, 116.1, 115.8, 106.5, 95.1, 79.8, 51.0; IR (KBr) ν: 3430, 2998, 2198, 1620, 1540, 1270, 1040, 760, 690 cm^－1; HRMS (ESI) calcd for C₃₂H₂₅N₄O (M+H)⁺ 481.2028, found 481.2026.

  4-(3-Methoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4c): White powder; m.p. 100~101 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.98 (s, 1H), 7.68 (d, J＝7.5 Hz, 2H), 7.60 (d, J＝7.0 Hz, 2H), 7.55~7.49 (m, 4H), 7.48~7.43 (m, 3H), 7.39 (t, J＝7.5 Hz, 1H), 7.29~7.20 (m, 3H), 7.17 (t, J＝8.0 Hz, 1H), 6.83~6.78 (m, 2H), 6.72~6.70 (m, 1H), 5.36 (s, 1H), 3.62 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 154.4, 144.6, 142.3, 142.0, 133.5, 133.3, 129.1, 127.9, 125.5, 124.9, 124.7, 124.6, 124.6, 124.0, 123.8, 123.6, 123.0, 122.8, 122.7, 122.0, 119.1, 117.1, 116.8, 115.1, 108.9, 107.1, 95.0, 80.1, 50.1; IR (KBr)v: 3432, 2998, 2199, 1622, 1547, 1247, 1045, 766, 698 cm^－1; HRMS (ESI) calcd for C₃₂H₂₅N₄O(M+H)⁺ 481.2028, found 481.2025.

  4-(4-Methoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4d): White powder; m.p. 121~122 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.94 (s, 1H), 7.68 (d, J＝7.0 Hz, 2H), 7.58 (d, J＝7.0 Hz, 2H), 7.53~7.50 (m, 4H), 7.47~7.37 (m, 4H), 7.19~7.27 (m, 3H), 7.17 (d, J＝7.0 Hz, 2H), 6.80 (d, J＝8.5 Hz, 2H), 5.31 (s, 1H), 3.65 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 158.5, 149.3, 147.5, 138.8, 138.6, 138.0, 134.4, 133.1, 130.7, 130.0, 129.9, 129.8, 129.4, 129.3, 129.2, 129.0, 128.8, 128.7, 128.2, 128.0, 127.9, 127.2, 124.3, 122.3, 121.3, 114.3, 100.4, 86.0, 55.4; IR (KBr) ν: 3431, 2998, 2199, 1628, 1531, 1273, 1045, 761, 697 cm^－1; HRMS (ESI) calcd for C₃₂H₂₅N₄O (M+H)⁺ 481.2028, found 481.2026.

  4-(3, 4-Dimethoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4e): White powder; m.p. 115~116 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.94 (s, 1H), 7.66 (d, J＝7.0 Hz, 2H), 7.62 (d, J＝7.0 Hz, 2H), 7.56~7.51 (m, 4H), 7.48~7.43 (m, 3H), 7.38 (t, J＝7.5 Hz, 1H), 7.29 (t, J＝7.5 Hz, 2H), 7.23 (t, J＝7.5 Hz, 1H), 6.74~6.72 (m, 1H), 5.33 (s, 1H), 3.63 (s, 3H), 3.57 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆)δ: 149.6, 148.7, 148.0, 147.6, 138.6, 138.5, 138.4, 134.4, 133.2, 130.7, 129.8, 129.3, 128.9, 128.2, 127.9, 127.4, 124.3, 121.4, 120.2, 112.4, 100.7, 85.6, 55.8, 55.8; IR (KBr)ν: 3421, 2998, 2199, 1675, 1551, 1247, 1044, 765, 694 cm^－1; HRMS (ESI) calcd for C₃₃H₂₇N₄O₂ (M+H)⁺ 511.2134, found 511.2132.

  4-(2, 3, 4-Trimethoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihyd-ro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4f): White powder; m.p. 119~120 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.88 (s, 1H), 7.67 (d, J＝7.0 Hz, 1H), 7.52~7.50 (m, 6H), 7.47~7.42 (m, 3H), 7.38 (t, J＝7.5 Hz, 1H), 7.24 (t, J＝7.0 Hz, 2H), 7.19 (t, J＝7.5 Hz, 1H), 6.85 (d, J＝9.0 Hz, 1H), 6.67 (d, J＝9.0 Hz, 1H), 5.50 (s, 1H), 3.79 (s, 3H), 3.68 (s, 3H), 3.65 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆)δ: 152.8, 149.8, 147.3, 141.5, 139.1, 138.7, 134.6, 133.2, 130.6, 130.0, 129.9, 129.8, 129.3, 129.1, 128.8, 128.6, 128.1, 127.8, 127.1, 124.8, 124.2, 121.6, 108.3, 100.5, 85.4, 61.5, 60.5, 56.1; IR (KBr) ν: 3431, 2998, 2199, 1620, 1541, 1247, 1045, 764, 697 cm^－1; HRMS (ESI) calcd for C₃₄H₂₉N₄O₃ (M+H)⁺ 541.2240, found 541.2242.

  4-(3, 4, 5-Trimethoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihyd-ro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4g): White powder; m.p. 108~109 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.99 (s, 1H), 7.68~7.66 (m, 4H), 7.62~7.60 (m, 2H), 7.54~7.49 (m, 5H), 7.40 (t, J＝7.0 Hz, 1H), 7.35 (t, J＝7.0 Hz, 2H), 7.29 (t, J＝7.0 Hz, 1H), 6.52 (s, 2H), 5.39 (s, 1H), 3.60 (s, 6H), 3.56 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 184.8, 158.5, 134.8, 133.0, 129.8, 127.4, 127.2, 126.6, 126.2, 126.0, 125.3, 123.0, 122.4, 113.3, 55.8, 31.1; IR (KBr) ν: 3431, 2998, 2198, 1655, 1551, 1207, 1040, 762, 696 cm^－1; HRMS (ESI) calcd for C₃₄H₂₉N₄O₃ (M+H)⁺ 541.2240, found 541.2243.

  4-(4-Ethoxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4h): White powder; m.p. 102~103 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.93 (s, 1H), 7.68 (d, J＝7.0 Hz, 2H), 7.58 (d, J＝7.0 Hz, 2H), 7.53~7.50 (m, 4H), 7.47~7.42 (m, 3H), 7.38 (t, J＝7.5 Hz, 1H), 7.25 (t, J＝7.5 Hz, 2H), 7.20 (t, J＝7.5 Hz, 1H), 7.25 (d, J＝8.5 Hz, 2H), 6.28 (d, J＝8.5 Hz, 2H), 5.30 (s, 1H), 3.92~3.88 (m, 2H), 1.23 (t, J＝7.0 Hz, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 157.8, 149.3, 147.5, 138.8, 138.6, 137.8, 134.4, 133.1, 130.7, 129.8, 129.3, 129.2, 128.9, 128.8, 128.7, 128.2, 127.9, 127.2, 124.3, 122.3, 121.3, 115.3, 114.8, 100.4, 86.0, 63.3, 15.1; IR (KBr) ν: 3432, 2989, 2199, 1629, 1546, 1257, 1055, 765, 695 cm^－1; HRMS (ESI) calcd for C₃₃H₂₇N₄O (M+H)⁺ 495.2185, found 495.2186.

  4-(4-Hydroxyphenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4i): White powder; m.p. 125~126 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.10 (s, 1H), 7.66 (d, J＝7.0 Hz, 4H), 7.58~7.44 (m, 8H), 7.39 (t, J＝7.5 Hz, 1H), 7.32~7.25 (m, 4H), 6.92 (t, J＝2.0 Hz, 1H), 6.86~6.84 (m, 1H), , 5.78 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 145.4, 144.5, 142.3, 133.2, 133.0, 128.9, 127.8, 125.6, 124.7, 124.6, 124.5, 124.1, 123.6, 123.5, 123.1, 122.7, 122.0, 121.9, 120.7, 119.2, 119.1, 117.2, 115.9, 95.2, 79.9; IR (KBr) ν: 3431, 2998, 2201, 1624, 1546, 1265, 1045, 762, 699 cm^－1; HRMS (ESI) calcd for C₃₁H₂₃N₄O (M+H)⁺ 467.1872, found 467.1870.

  4-(p-Tolyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyra-zolo-[3, 4-b]pyridine-5-carbonitrile (4j): White powder; m.p. 107~104 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.99 (s, 1H), 7.72 (d, J＝7.5 Hz, 2H), 7.62 (d, J＝7.0 Hz, 2H), 7.58~7.55 (m, 4H), 7.52~7.42 (m, 4H), 7.31~7.23 (m, 3H), 7.17 (d, J＝8.0 Hz, 2H), 7.09 (d, J＝8.0 Hz, 2H), 5.36 (s, 1H), 2.23 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 149.5, 142.8, 138.8, 138.6, 136.4, 134.4, 133.1, 130.7, 129.8, 129.6, 129.3, 128.8, 128.2, 128.0, 127.9, 127.2, 124.3, 85.9, 77.9, 21.1; IR (KBr) ν: 3433, 2988, 2198, 1605, 1521, 1253, 1040, 763, 697 cm^－1; HRMS (ESI) calcd for C₃₂H₂₅N₄ (M+H)⁺465.2079, found 465.2080.

  4-(4-(tert-Butyl)phenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4k): White powder; m.p. 141~142 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.03 (s, 1H), 7.72 (d, J＝7.5 Hz, 2H), 7.64 (d, J＝7.5 Hz, 2H), 7.57 (t, J＝7.5 Hz, 4H), 7.51~7.43 (m, 4H), 7.33~7.21 (m, 7H), 5.37 (s, 1H), 1.23 (s, 9H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 144.5, 144.3, 142.0, 137.6, 133.6, 133.4, 129.1, 127.9, 125.5, 124.6, 124.0, 123.7, 122.7, 122.4, 121.9, 120.6, 119.1, 117.8, 116.2, 110.3, 95.2, 80.4, 29.4, 28.3; IR (KBr) ν: 3443, 2998, 2198, 1602, 1525, 1254, 1040, 763, 697 cm^－1; HRMS (ESI) calcd for C₃₅H₃₁N₄ (M+H)⁺ 507.2549, found 507.2548.

  4-(4-Chlorophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-py-razolo[3, 4-b]pyridine-5-carbonitrile (4l): White powder; m.p. 101~102 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.05 (s, 1H), 7.70 (d, J＝7.5 Hz, 2H), 7.59 (d, J＝7.0 Hz, 2H), 7.54 (t, J＝7.0 Hz, 4H), 7.50~7.45 (m, 5H), 7.31~7.23 (m, 3H), 7.42 (t, J＝7.0 Hz, 1H), 5.47 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 144.6, 142.3, 139.3, 133.6, 133.3, 129.0, 127.7, 126.7, 125.5, 124.8, 124.6, 124.5, 124.1, 123.7, 123.6, 123.5, 123.4, 123.1, 122.9, 122.8, 121.9, 119.2, 118.9, 94.5, 79.9; IR (KBr) ν: 3432, 2938, 2199, 1665, 1546, 1267, 1045, 765, 695 cm^－1; HRMS (ESI) calcd for C₃₁H₂₂ClN₄ (M+H)⁺ 485.1513, found 485.1516.

  4-(2-Bromophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-py-razolo[3, 4-b]pyridine-5-carbonitrile (4m): White powder; m.p. 112~113 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.08 (s, 1H), 7.68 (d, J＝7.5 Hz, 2H), 7.54~7.19 (m, 16H), 7.08~7.04 (m, 1H), 5.83 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 139.3, 138.5, 137.5, 134.3, 132.8, 130.7, 129.9, 129.8, 129.5, 129.3, 129.1, 128.8, 128.6, 128.3, 128.1, 128.0, 127.2, 124.5, 120.5, 97.4, 86.0; IR (KBr) ν: 3451, 2958, 2198, 1665, 1547, 1257, 1040, 760, 695 cm^－1; HRMS (ESI) calcd for C₃₁H₂₂BrN₄ (M+H)⁺: 529.1028, found 529.1030.

  4-(3-Bromophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-py-razolo[3, 4-b]pyridine-5-carbonitrile (4n): White powder; m.p. 105~106 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.05 (s, 1H), 7.70 (d, J＝7.5 Hz, 2H), 7.59 (d, J＝7.0 Hz, 2H), 7.54 (t, J＝7.0 Hz, 4H), 7.50~7.45 (m, 5H), 7.31~7.23 (m, 3H), 7.42 (t, J＝7.0 Hz, 1H), 5.47 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 144.9, 142.8, 142.4, 133.5, 133.3, 129.0, 127.6, 126.0, 125.6, 125.1, 124.6, 124.1, 123.6, 123.5, 123.1, 122.8, 122.2, 122.0, 119.2, 117.0, 115.8, 94.4, 79.6; IR (KBr) ν: 3442, 2978, 2198, 1625, 1527, 1250, 1025, 762, 691 cm^－1; HRMS (ESI) calcd for C₃₁H₂₂BrN₄ (M+H)⁺ 529.1028, found 529.1029.

  4-(4-Bromophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-py-razolo[3, 4-b]pyridine-5-carbonitrile (4o): White powder; m.p. 123~124 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.05 (s, 1H), 7.70 (d, J＝7.5 Hz, 2H), 7.59 (d, J＝7.0 Hz, 2H), 7.54 (t, J＝7.0 Hz, 4H), 7.50~7.45 (m, 5H), 7.31~7.23 (m, 3H), 7.42 (t, J＝7.0 Hz, 1H), 5.47 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 144.7, 142.3, 139.7, 133.6, 133.3, 129.0, 127.7, 126.6, 125.5, 125.2, 124.6, 124.1, 123.6, 123.5, 123.1, 122.8, 121.9, 119.2, 115.8, 115.3, 94.4, 79.8; IR (KBr) ν: 3431, 2978, 2199, 1605, 1540, 1257, 1042, 762, 698 cm^－1; HRMS (ESI) calcd for C₃₁H₂₂BrN₄ (M+H)⁺ 529.1028, found 529.1032.

  4-(4-Nitrophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyra-zolo[3, 4-b]pyridine-5-carbonitrile (4p): Yellow powder; m.p. 104~105 ℃; ¹H NMR (500 MHz, DMSO-d₆)δ: 10.17 (s, 1H), 8.11 (d, J＝9.0 Hz, 2H), 7.69 (d, J＝7.5 Hz, 2H), 7.57~7.51 (m, 8H), 7.49~7.39 (m, 4H), 7.26~7.18 (m, 3H), 5.70 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆)δ: 147.2, 145.3, 142.4, 141.7, 133.6, 133.2, 128.8, 127.5, 125.6, 125.1, 124.7, 124.6, 124.3, 124.1, 123.6, 123.5, 123.2, 122.9, 121.9, 119.5, 119.4, 119.3, 119.0, 115.6, 93.8, 78.9; IR (KBr) ν: 3431, 2998, 2169, 1635, 1540, 1250, 1075, 762, 696 cm^－1; HRMS (ESI) calcd for C₃₁H₂₂N₅O₂ (M+H)⁺496.1773, found 496.1771.

  4-(4-Cyanophenyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-py-razolo[3, 4-b]pyridine-5-carbonitrile (4q): White powder; m.p. 140~141 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.12 (s, 1H), 7.73~7.68 (m, 4H), 7.60 (d, J＝8.0 Hz, 1H), 7.56~7.51 (m, 6H), 7.48~7.43 (m, 4H), 7.43~7.39 (m, 1H), 7.30~7.19 (m, 3H), 5.61 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 147.1, 138.4, 138.0, 133.6, 132.5, 130.6, 129.5, 129.3, 128.9, 128.8, 128.4, 128.3, 127.7, 126.7, 124.0, 121.8, 120.4, 118.7, 112.2, 111.9, 109.8, 101.9, 98.6, 83.8; IR (KBr) ν: 3431, 2998, 2195, 1645, 1521, 1207, 1065, 761, 693 cm^－1; HRMS (ESI) calcd for C₃₂H₂₂N₅ (M+H)⁺ 476.1875, found 476.1873.

  4-(Furan-2-yl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo-[3, 4-b]pyridine-5-carbonitrile (4r): Brown powder; m.p. 112~113 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.09 (s, 1H), 7.69 (t, J＝7.5 Hz, 4H), 7.61 (d, J＝7.0 Hz, 2H), 7.57~7.49 (m, 6H), 7.43 (t, J＝7.0 Hz, 1H), 7.37~7.29 (m, 3H), 6.31 (s, 1H), 6.20 (t, J＝3.0 Hz, 1H), 5.64 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 150.9, 145.6, 142.4, 137.8, 133.5, 129.0, 127.8, 125.6, 124.6, 124.1, 123.6, 123.5, 123.1, 122.7, 122.0, 119.1, 115.8, 105.7, 101.7, 92.5, 77.0; IR (KBr) ν: 3441, 2955, 2198, 1660, 1545, 1252, 1042, 765, 690 cm^－1; HRMS (ESI) calcd for C₂₉H₂₁N₄O (M+H)⁺ 441.1715, found 441.1713.

  4-(Thiophen-2-yl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyra-zolo[3, 4-b]pyridine-5-carbonitre (4s): Brown powder; m.p. 110~111 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.89 (s, 1H), 7.67 (d, J＝8.0 Hz, 2H), 7.59~7.50 (m, 5H), 7.47~7.42 (m, 2H), 7.38 (t, J＝7.0 Hz, 1H), 7.27~7.13 (m, 4H), 7.03 (t, J＝7.5 Hz, 2H), 6.61 (t, J＝7.5 Hz, 2H), 5.22 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 150.9, 143.4, 141.8, 133.1, 132.9, 128.8, 127.5, 126.0, 125.0, 124.3, 124.2, 123.8, 123.6, 123.5, 123.3, 123.1, 123.0, 122.5, 122.4, 122.2, 121.5, 118.8, 116.1, 115.7, 110.0, 109.5, 94.9, 80.5; IR (KBr) ν: 3431, 2995, 2190, 1615, 1524, 1255, 1025, 752, 686 cm^－1; HRMS (ESI) calcd for C₂₉H₂₁N₄ S (M+H)⁺ 457.1487, found 457.1490.

  4-(Pyridin-4-yl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazo-lo[3, 4-b]pyridine-5-carbonitrile (4t): Brown powder; m.p. 120~121 ℃; ¹H NMR (500 MHz, DMSO-d₆)δ: 10.12 (s, 1H), 8.11 (d, J＝9.0 Hz, 2H), 7.69 (d, J＝7.5 Hz, 2H), 7.57~7.51 (m, 8H), 7.48~7.39 (m, 4H), 7.25~7.20 (m, 3H), 5.70 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆)δ: 152.4, 150.6, 147.6, 146.9, 138.9, 138.5, 134.1, 132.8, 130.9, 130.9, 129.8, 129.6, 129.4, 129.3, 128.9, 128.8, 128.5, 128.1, 127.2, 124.5, 124.3, 120.8, 99.1, 84.2; IR (KBr) ν: 3431, 2988, 2198, 1655, 1545, 1257, 1070, 765, 694 cm^－1; HRMS (ESI) calcd for C₃₀H₂₂N₅ (M+H)⁺ 452.1875, found 452.1878.

  4-Cyclohexyl-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo-[3, 4-b]pyridine-5-carbonitrile (4u): White powder; m.p. 96~97 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 9.92 (s, 1H), 7.76 (d, J＝7.5 Hz, 2H), 7.68~7.64 (m, 4H), 7.55~7.52 (m, 5H), 7.46 (t, J＝7.5 Hz, 2H), 7.42~7.36 (m, 2H), 4.23 (t, J＝3.0 Hz, 1H), 1.75~1.67 (m, 2H), 1.58~1.53 (m, 2H), 1.44~1.42 (m, 2H), 1.33~1.24 (m, 1H), 1.10~0.99 (m, 4H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 152.7, 147.2, 139.4, 138.6, 134.5, 134.1, 130.9, 129.8, 129.5, 129.1, 128.9, 128.3, 127.8, 127.2, 123.1, 122.7, 122.1, 100.1, 81.2, 47.3, 30.8, 29.9, 28.6, 26.7, 26.5, 26.4; IR (KBr) ν: 3435, 3235, 2930, 2195, 1618, 1596, 1459, 1457, 764, 696 cm^－1; HRMS (ESI) calcd for C₃₁H₂₉N₄ (M+H)⁺ 457.2392, found 457.2396.

  4-(Phenylethynyl)-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyra-zolo[3, 4-b]pyridine-5-carbonitrile (4v): Yellow powder; m.p. 222~223 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.07 (s, 1H), 7.93 (d, J＝7.5 Hz, 2H), 7.68 (d, J＝7.5 Hz, 4H), 7.58~7.55 (m, 5H), 7.50 (t, J＝9.5 Hz, 2H), 7.46~7.39 (m, 2H), 7.34~7.29 (m, 3H), 7.17 (d, J＝6.5 Hz, 2H), 5.73 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 151.1, 147.8, 145.7, 138.4, 137.9, 134.1, 132.9, 131.6, 130.9, 129.8, 129.3, 129.1, 129.0, 128.9, 128.9, 128.5, 128.1, 127.5, 124.5, 122.6, 96.8, 90.7, 80.9; IR (KBr) ν: 3473, 2954, 2199, 1628, 1544, 1265, 1072, 755, 692 cm^－1; HRMS (ESI) calcd for C₃₃H₂₃N₄ (M+H)⁺ 475.1923, found 475.1925.

  6-(Pyridin-4-yl)-1, 3, 4-triphenyl-4, 7-dihydro-1H-pyrazo-lo[3, 4-b]pyridine-5-carbonitrile (4w): White powder; m.p. 165~166 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.17 (s, 1H), 8.77 (d, J＝1.5 Hz, 1H), 8.69 (dd, J＝1.0, 4.5 Hz, 1H), 7.99 (d, J＝9.0Hz, 1H), 7.74 (d, J＝7.5 Hz, 2H), 7.61~7.57 (m, 4H), 7.54~7.51 (m, 1H), 7.46 (t, J＝7.5 Hz, 1H), 7.33~7.25 (m, 7H), 7.18 (t, J＝7.0 Hz, 1H), 5.48 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 160.0, 151.4, 149.6, 147.7, 147.0, 145.4, 138.6, 138.4, 137.2, 133.0, 130.4, 129.8, 129.0, 128.7, 128.3, 128.1, 127.5, 127.2, 124.5, 123.8, 120.8, 120.0, 100.0, 86.7; IR (KBr) ν: 3431, 2993, 2198, 1625, 1539, 1253, 1059, 762, 694 cm^－1; HRMS (ESI) calcd for C₃₀H₂₂N₅ (M+H)⁺ 452.1875, found 452.1878.

  6-(Pyridin-4-yl)-1, 3-diphenyl-4-(p-tolyl)-7, 7a-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4x): White powder; m.p. 134~135 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.13 (s, 1H), 8.76 (d, J＝1.5 Hz, 1H), 8.69 (d, J＝5.0 Hz, 1H), 7.98 (d, J＝7.5 Hz, 1H), 7.74 (d, J＝8.0 Hz, 2H), 7.63 (d, J＝7.0 Hz, 2H), 7.58 (t, J＝8.0 Hz, 2H), 7.53~7.51 (m, 1H), 7.46 (t, J＝7.5 Hz, 1H), 7.32~7.25 (m, 3H), 7.20 (d, J＝8.0 Hz, 2H), 7.10 (d, J＝8.0 Hz, 2H), 5.42 (s, 1H), 2.23 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 151.4, 149.6, 147.6, 146.8, 142.6, 138.6, 138.4, 137.2, 136.5, 133.0, 130.4, 129.9, 129.7, 129.6, 128.7, 128.3, 128.1, 128.1, 127.2, 124.4, 123.8, 120.8, 100.8, 87.0, 21.1; IR (KBr) ν: 3401, 2894, 2199, 1624, 1541, 1281, 1027, 765, 695 cm^－1; HRMS (ESI) calcd for C₃₁H₂₄N₅ (M+H)⁺ 466.2032, found 466.2033.

  4-(4-Nitrophenyl)-1, 3-diphenyl-6-(pyridin-4-yl)-4, 7-di-hydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (4y): Ye-llow powder; m.p. 171~172 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.33 (s, 1H), 8.78 (s, 1H), 8.70 (d, J＝5.0 Hz, 1H), 8.16 (d, J＝8.5 Hz, 2H), 8.01 (d, J＝8.0 Hz, 1H), 7.75 (d, J＝8.0 Hz, 2H), 7.63~7.58 (m, 6H), 7.54~7.52 (m, 1H), 7.47 (t, J＝7.5, 1H), 7.32~7.24 (m, 3H), 5.80 (s, 1H); ¹³C NMR (125 MHz, DMSO-d₆)δ: 152.2, 151.5, 149.6, 147.9, 147.8, 147.0, 138.6, 138.3, 137.2, 132.7, 137.2, 132.7, 130.2, 129.9, 129.7, 128.8, 128.5, 128.3, 127.5, 127.2, 124.6, 124.3, 123.8, 120.4, 98.9, 88.9, 85.2; IR (KBr) ν: 3364, 2966, 2200, 1626, 1546, 1346, 1108, 767, 696 cm^－1; HRMS (ESI) calcd for C₃₀H₂₁N₆O₂ (M+H)⁺ 497.1726, found 497.1723.

  4, 4'-(1, 4-Phenylene)bis(1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile) (5a): White pow-der; m.p. 231~231 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.02 (s, 2H), 7.74~7.69 (m, 4H), 7.59~7.52 (m, 8H), 7.50~7.40 (m, 12H), 7.28~7.14 (m, 10H), 5.28 (d, J＝3 Hz, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 154.2, 149.7, 147.8, 147.6, 146.2, 144.8, 144.3, 144.3, 138.9, 138.6, 134.3, 134.0, 130.7, 129.8, 129.3, 128.8, 128.6, 128.4, 128.1, 127.9, 127.2, 124.4, 124.4, 100.1, 89.4, 85.3; IR (KBr) ν: 3411, 2858, 2201, 1625, 1545, 1250, 994, 766, 696 cm^－1; HRMS (ESI) calcd for C₅₆H₃₉N₈ (M+H)⁺ 823.3298, found 823.3301.

  7-(4'-(5-Cyano-1, 3, 6-triphenyl-4, 7-dihydro-1H-pyrazo-lo[3, 4-b]pyridin-4-yl)-[1, 1'-biphenyl]-4-yl)-1, 3, 5-triphen-yl-4, 7-dihydro-1H-pyrazolo[4, 3-b]pyridine-6-carbonitrile (5b): Yellow powder; m.p. 175~176 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 10.11 (s, 2H), 7.75 (d, J＝8.0 Hz, 4H), 7.64 (d, J＝7.5 Hz, 4H), 7.58 (t, J＝8.0 Hz, 12H), 7.53~7.43 (m, 10H), 7.36 (d, J＝8.0 Hz, 4H), 7.30 (t, J＝7.0 Hz, 4H), 5.47 (s, 2H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 153.9, 149.7, 147.5, 144.8, 138.9, 138.5, 134.3, 133.0, 130.7, 129.8, 129.3, 128.8, 128.7, 128.6, 128.3, 128.0, 124.4, 121.2, 100.1, 100.0, 85.5; IR (KBr) ν: 3421, 2988, 2208, 1625, 1545, 1275, 1027, 765, 695 cm^－1; HRMS (ESI) calcd for C₆₂H₄₃N₈ (M+H)⁺ 899.3611, found 899.3618.

  1, 3-Dimethyl-4, 6-diphenyl-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile (6): White powder; m.p. 194~195 ℃; ¹H NMR (500 MHz, DMSO-d₆) δ: 7.96~7.83 (m, 2H), 7.68~7.54 (m, 8H), 4.05 (s, 3H), 1.98 (s, 3H); ¹³C NMR (125 MHz, DMSO-d₆) δ: 160.0, 152.5, 150.6, 141.9, 138.4, 134.3, 130.4, 130.3, 129.8, 129.5, 128.9, 128.8, 118.2, 111.8, 100.4, 34.1, 14.5; IR (KBr) ν: 3477, 2222, 1653, 1563, 1444, 1383, 777, 706 cm^－1; HRMS (ESI) calcd for C₂₄H₁₆N₄ (M+H)⁺ 325.1453; found 325.1458.

  Supporting Information The copy of ¹H NMR and¹³C NMR spectra of all compounds. The Supporting Information is available free of charge via the Internet at http://sioc-journal.cn.

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• 

  Scheme 1  Proline/oxalic acid catalyzed synthesis of 4, 7-dihy-dro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives

  下载: 全尺寸图片 幻灯片
  

  Scheme 2  Synthesis of bis(4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile) derivatives

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  Scheme 3  Synthesis of 1, 3-dimethyl-4, 6-diphenyl-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile

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  Scheme 4  Plausible reaction mechanism

  下载: 全尺寸图片 幻灯片

  Table 1.  Reaction of benzaldehyde, 3-oxo-3-phenylpropanenitrile and 1, 3-diphenyl-1H-pyrazol-5-amine under different conditions^a

  Entry	Catalyst	Solvent	Temp./℃	Time/h	Yieldb/%
  1	No	No	100	8.0	Trace
  2	No	H2O	Reflux	8.0	Trace
  3	No	THF	Reflux	8.0	13
  4	No	DMF	Reflux	8.0	25
  5	No	MeOH	Reflux	8.0	54
  6	No	EtOH	Reflux	8.0	58
  7	FeCl3	EtOH	Reflux	4.0	79
  8	NH2SO3H	EtOH	Reflux	4.0	80
  9	CH3SO3H	EtOH	Reflux	4.0	82
  10	p-TSA	EtOH	Reflux	4.0	83
  11	CH3COOH	EtOH	Reflux	4.0	85
  12	L-Lysine	EtOH	Reflux	4.0	84
  13	Oxalic acid	EtOH	Reflux	4.0	81
  14	L-Proline	EtOH	Reflux	4.0	86
  15	L-Proline/oxalic acid	EtOH	Reflux	4.0	92
  16	L-Proline/oxalic acid	EtOH	r.t.	4.0	24
  17	L-Proline/oxalic acid	EtOH	40	4.0	56
  18	L-Proline/oxalic acid	EtOH	60	4.0	73
  19c	L-Proline /oxalic acid	EtOH	Reflux	4.0	89
  20d	L-Proline/oxalic acid	EtOH	Reflux	4.0	92
  21e	L-Proline/oxalic acid	EtOH	Reflux	4.0	93
  22f	L-Proline/oxalic acid	EtOH	Reflux	4.0	92, 91, 91, 90, 89
  a Reaction conditions: benzaldehyde (1 mmol), 3-oxo-3-phenylpropanenitrile (1 mmol) and 1, 3-diphenyl-1H-pyrazol-5-amine (1 mmol), catalyst (20 mol%) in solvent (2 mL) otherwise specified in the table. b Isolated yields. c 10 mol% catalyst was used. d 30 mol% catalyst was used. e The reaction was carried out in 10 mmol scale. f Catalyst was reused for five times.

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  Table 2.  Synthesis of 4, 7-dihydro-1H-pyrazolo[3, 4-b]pyridine-5-carbonitrile derivatives catalyzed by oxalic acid/proline^a

  Entry	Aldehyde	X	Product	Time/h	Yieldb/%
  1	PhCHO	CH	4a	1.0	95
  2	2-MeOC6H4CHO	CH	4b	1.0	90
  3	3-MeOC6H4CHO	CH	4c	1.0	94
  4	4-MeOC6H4CHO	CH	4d	1.0	93
  5	3, 4-(MeO)2C6H3CHO	CH	4e	1.5	90
  6	2, 3, 4-(MeO)3C6H2CHO	CH	4f	1.5	82
  7	3, 4, 5-(MeO)3C6H2CHO	CH	4g	1.5	85
  8	4-EtOC6H4CHO	CH	4h	1.0	91
  9	4-HO-C6H4CHO	CH	4i	1.0	91
  10	4-MeC6H4CHO	CH	4j	1.0	92
  11	4-Me3CC6H4CHO	CH	4k	1.0	90
  12	4-ClC6H4CHO	CH	4l	1.0	90
  13	2-BrC6H4CHO	CH	4m	1.0	90
  14	3-BrC6H4CHO	CH	4n	1.0	92
  15	4-BrC6H4CHO	CH	4o	1.0	95
  16	4-O2NC6H4CHO	CH	4p	1.0	87
  17	4-NCC6H4CHO	CH	4q	1.0	88
  18	Furan-2-carbaldehyde	CH	4r	2.0	72
  19	Thiophene-2-carbaldehyde	CH	4s	2.0	76
  20	4-Pyridine-carbaldehyde	CH	4t	2.0	79
  21	Cyclohexanecarbaldehyde	CH	4u	3.0	75
  22	3-Phenylpropiolaldehyde	CH	4v	2.0	82
  23	PhCHO	N	4w	1.5	90
  24	4-MeC6H4CHO	N	4x	1.5	91
  25	4-O2NC6H4CHO	N	4y	1.5	93
  a Reaction conditions: aldehyde (1 mmol), 3-oxopropanenitrile (1 mmol), 1H-pyrazol-5-amine (1 mmol) and oxalic acid/proline (0.2 mmol) in refluxing EtOH (2 mL). b Isolated yield.

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•