Tin (IV) Chloride-Promoted One-Pot Synthesis of Novel Tacrine Analogues

Abstract

A facile synthesis of potential acetylcholinesterase (AChE) inhibitors, the tacrine analogues 3a-p, has been accomplished by direct cyclocondensation of 1-aryl-4-cyano-5-aminopyrazole with β-ketoesters using tin(IV) chloride as catalyst. The structures of all the compounds have been confirmed by IR, ¹H- and ¹³C-NMR.

1. Introduction

Alzheimer’s disease (AD), the most common form of dementia among the elderly, is a progressive, degenerative disorder of the brain with a loss of memory and cognition [1]. Tacrine is a reversible inhibitor of acetylcholinesterase (AChE) that was launched in 1993 as the first drug for the treatment of AD [2]. The evaluation of the clinical effects of tacrine has shown efficacy in delaying the deterioration of the symptoms of AD, but the poor selectivity of this drug for AChE has resulted in a number of side effects, specially hepatotoxicity [3], and current research is focused on developing new AChE inhibitors with improved activity and reduced adverse side effects, therefore novel tacrine analogues have been reported [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18].

Friedlander annulation is one of the simplest and most straightforward protocols for the preparation of quinoline derivatives [19,20]. Although it has been known for more than a century, it is still a hotspot of research. Herein, we report that the Friedlander annulation of 1-aryl-4-cyano-5-aminopyrazole with β-ketoesters using SnCl₄ as catalyst afforded the novel tacrine analogues 3a-p in good yields.

2. Results and Discussion

The main synthetic approach to tacrine analogues is the cyclocondensation of o-aminonitrile derivatives with ketones using anhydrous AlCl₃ as catalyst, but that method gives low to moderate yields [4,5,6,7,8,9,10,11,12,13,14,15,16,17,18]. Cabrera and co-workers [21] have reported that the synthesis of 4-aminoquinolines from 2-aminobenzonitrile and β-dicarbonyl compounds could be accomplished using Lewis acids as catalysts. They found that SnCl₄ was a very effective catalyst for the preparation of the target compounds compared with other Lewis acids.

For the investigation of reaction conditions for cyclocondensation of 1-aryl-4-cyano-5-amino-pyrazole with β-ketoesters, we chose the reaction of 1-phenyl-4-cyano-5-aminopyrazole (1a) with methyl acetoacetate as a model reaction. Because the choice of the catalyst played a crucial role, we initially studied the effect of several catalysts on the yields and found the use of anhydrous AlCl₃, ZnCl₂ and TiCl₄ to be much less effective and tacrine analogue 3a was obtained in less than 43% yield. Moreover, none of the product desired 3a was obtained when we used CuCl and CuCl₂ as catalysts. However, when a mixture of 1-phenyl-4-cyano-5-aminopyrazole (1a) and methyl acetoacetate in toluene was stirred under reflux in the presence of SnCl₄, the reaction was complete within 3 h and after work up, the product 3a was obtained in 78% yield (

Table 1. Effect of the catalyst on the yields. ^a

Entry	Catalyst	Time(h)	Yield(%)b
1 2 3 4 5 6	CuCl CuCl2 AlCl3 ZnCl2 TiCl4 SnCl4	3 3 3 3 3 3	0 0 36 23 43 78

^a All reactions were carried out using 1a (10 mmol), methyl acetoacetate (10 mmol), catalyst (20 mmol) and toluene (20 mL), reflux for 3 h; ^b Isolated yields.

).

A profound solvent effect on the reaction was observed. We initially studied the effect on the reaction of non-polar solvents, such as DCM, DCE, THF and toluene, in which SnCl₄ is easily dissolved. Then we went on to study the polar solvent DMF. The results are summarized in

Table 2. Effect of the solvent on the yields. ^a

Entry	Solvent	Time (h)	Yield (%)b
1 2 3 4 5	DCM DCE THF Toluene DMF	3 3 3 3 3	53 68 51 78 0

^a All reactions were carried out using 1a (10 mmol), methyl acetoacetate (10 mmol), SnCl₄ (20 mmol) and solvent (20 mL), reflux for 3 h; ^b Isolated yields.

. These results suggest that the solvent had a dramatic effect on the yields. Toluene was found to be the best solvent.

Under the optimized reaction conditions (SnCl₄ as catalyst and anhydrous toluene as solvent, reflux for 3 h), a series of reactions between 1-aryl-4-cyano-5-aminopyrazoles and β-ketoesters were tested and a series of tacrine analogues 3 was thus prepared in good yields, regardless of the position of the group R¹ on the aromatic ring. The results were summarized in

Table 3. Cyclocondensation of substituted o-aminobenzonitrile and β-ketoesters. ^a

Entry	R1	R2	Product(3)	Yield(%)b
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16	H 4-CH3 3-CH3 4-Cl 3-Cl 2-Cl 4-NO2 2,4-NO2 H 4-CH33 -CH3 4-Cl 3-Cl 2-Cl 4-NO2 2,4-NO2	Me Me Me Me Me Me Me Me Et Et Et Et Et Et Et Et	3a 3b 3c 3d 3e 3f 3g 3h 3i 3j 3k 3l 3m 3n 3o 3p	78 75 70 74 72 65 62 58 76 74 71 75 73 64 60 57

^a All reactions were carried out using 1a (10 mmol), β-ketoesters (10 mmol), SnCl₄ (20 mmol) and toluene (20 mL), reflux for 3 h; ^b Isolated yields.

.

The mechanism of formation of tacrine analogue 3 can be explained by Scheme 2. The attack of the amino group of 1 onto the carbonyl carbon atom of 2 gave intermediate I, from which product 3 was obtained through the Friedlander reaction.

3. Experimental

3.1. General

All melting points were determined on an XT-4A apparatus. TLC was performed using precoated silica gel GF₂₅₄ (0.25 mm), column chromatography was performed using silica gel (200–300 mesh). The ¹H- and ¹³C-NMR spectra were measured at 300 and 75 MHz, respectively, on a Bruker Advance 300 spectrometer at 25 °C, using TMS as internal standard. J-values are given in Hz. The IR spectra were taken on a Bruker Vector 55 spectrometer. 1-Aryl-4-cyano-5-aminopyrazoles 1 were prepared according to a reported procedure [22].

3.2. Typical procedure

1-Aryl-4-cyano-5-aminopyrazole 1 (10 mmol) and SnCl₄ (2.3 mL, 20 mmol) were added to a stirred solution of β-ketoester (10 mmol) in dry toluene (20 mL). The reaction mixture was stirred under nitrogen at room temperature for 30 min and then heated under reflux for 3 h. The reaction mixture was cooled and dispersed into water and titrated to pH 12–13 with a saturated aqueous solution of Na₂CO₃. After filtration, the filtrate was extracted three times with ethyl acetate, the organic layers were dried and evaporated at reduced pressure to give the solid product. The product was purified by silica gel column chromatography to give 3a-p.

Methyl 4-amino-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3a). Colorless solid. m.p. 125–126 °C. ¹H-NMR (CDCl₃) δ: 8.24 (d, J = 6.9 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.41–7.48 (m, 2H, Ar-H), 7.23–7.28 (m, 1H, Ar-H), 6.74 (br, 2H, -NH₂), 3.90 (s, 3H, -OCH₃), 2.80 (s, 3H, -CH₃). ¹³C-NMR (CDCl₃) δ: 169.9, 163.1, 151.8, 150.0, 138.7, 131.6, 128.8, 126.3, 121.6, 105.3, 101.2, 51.6, 28.1. MS-ESI (m/z, relative intensity, %): 285 (M⁺+3) (3), 284 (M⁺+2) (18), 283 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,451, 3,330 (NH₂), 3,111 (ArH), 2,976, 2,926 (CH₃), 1,665 (C=O), 1,590, 1,495, 1,460 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Methyl 4-amino-6-methyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3b). Colorless solid. m.p. 167–168 °C. ¹H-NMR (CDCl₃) δ: 8.08 (d, J = 7.2 Hz, 2H, Ar-H), 8.05 (s, 1H, pyrazole H), 7.25–7.29 (m, 2H, Ar-H), 6.74 (br, 2H, -NH₂), 3.91 (s, 3H, -OCH₃), 2.80 (s, 3H, pyridine-CH₃), 2.38 (s, 3H, benzene-CH₃). ¹³C-NMR (CDCl₃) δ: 169.2, 162.1, 151.9, 149.5, 136.3, 135.4, 130.6, 128.9, 121.0, 104.7, 100.5, 51.5, 27.9, 20.8. MS-ESI (m/z, relative intensity, %): 299 (M⁺+3) (3), 298 (M⁺+2) (20), 297 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,452, 3,333 (NH₂), 3,110 (ArH), 2,976, 2,925 (CH₃), 1,660 (C=O), 1,590, 1,495, 1,460 (C=N and aromatic ring skeleton vibration), 1,246 (O-CH₃).

Methyl 4-amino-6-methyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3c). Colorless solid. m.p. 151–153 °C. ¹H-NMR (CDCl₃) δ: 8.07 (d, J = 7.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.33–7.39 (m, 1H, Ar-H), 7.11–7.16 (m, 1H, Ar-H), 6.72 (br, 2H, -NH₂), 3.91 (s, 3H, -OCH₃), 2.82 (s, 3H, pyridine-CH₃), 2.40 (s, 3H, benzene-CH₃). ¹³C-NMR (CDCl₃) δ: 169.0, 162.1, 151.0, 149.5, 138.6, 131.4, 128.1, 126.2, 125.1, 121.5, 118.7, 104.9, 101.0, 51.8, 28.1, 21.0. MS-ESI (m/z, relative intensity, %): 299 (M⁺+3) (2), 298 (M⁺+2) (22), 297 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,332 (NH₂), 3,112 (ArH), 2,978, 2,923 (CH₃), 1,672 (C=O), 1,596, 1,497, 1,465 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Methyl 4-amino-1-(4-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3d). Colorless solid. m.p. 160–162 °C. ¹H-NMR (CDCl₃) δ: 8.26 (d, J = 7.2 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.40–7.48 (m, 2H, Ar-H), 6.72 (br, 2H, -NH₂), 3.91 (s, 3H, -OCH₃), 2.81 (s, 3H, -CH₃). ¹³C-NMR (CDCl₃) δ: 168.8, 161.7, 151.2, 135.0, 131.7, 130.6, 127.9, 121.0, 118.2, 104.9, 100.4, 51.7, 28.0. MS-ESI (m/z, relative intensity, %): 320 (9), 319 (32), 317 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,451, 3,330 (NH₂), 3,111 (ArH), 2,976, 2,926 (CH₃), 1,665 (C=O), 1,592, 1,494, 1,458 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Methyl 4-amino-1-(3-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3e). Colorless solid. m.p. 127–128 °C. ¹H-NMR (CDCl₃) δ: 8.36–8.40 (m, 1H, Ar-H), 8.27–8.31 (m, 1H, Ar-H), 8.05 (s, 1H, pyrazole H), 7.40–7.43 (m, 1H, Ar-H), 7.24–7.26 (m, 1H, Ar-H), 6.74 (br, 2H, -NH₂), 3.90 (s, 3H), 2.82 (s, 3H, -CH₃). ¹³C-NMR (CDCl₃) δ: 168.9, 161.7, 151.1, 132.7, 131.5, 130.6, 130.1, 129.6, 128.4, 125.6, 121.7, 120.8, 118.4, 51.7, 28.0. MS-ESI (m/z, relative intensity, %): 319 (7), 318 (33), 317 (M⁺+1) (100). IR (KBr) ν: 3,453, 3,333 (NH₂), 3,110 (ArH), 2,976, 2,924 (CH₃), 1,668 (C=O), 1,592, 1,496, 1,461 (C=N and aromatic ring skeleton vibration), 1,258 (O-CH₃).

Methyl 4-amino-1-(2-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3f). Color-less solid. m.p. 154–155 °C. ¹H-NMR (CDCl₃) δ: 8.12 (s, 1H, Ar-H), 8.05 (s, 1H, pyrazole H), 7.55–7.58 (m, 1H, Ar-H), 7.39–7.42 (m, 2H, Ar-H), 6.74 (br, 2H, -NH₂), 3.90 (s, 3H, -OCH₃), 2.80 (s, 3H, -CH₃). ¹³C-NMR (CDCl₃) δ: 169.2, 162.8, 151.4, 151.3, 135.9, 131.7, 132.1, 130.5, 129.4, 129.1, 126.4, 103.1, 100.9, 51.6, 27.9. MS-ESI (m/z, relative intensity, %): 319 (8), 318 (33), 317 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,451, 3,330 (NH₂), 3,112 (ArH), 2,975, 2,923 (CH₃), 1,665 (C=O), 1,591, 1,495, 1,458 (C=N and aromatic ring skeleton vibration), 1,262 (O-CH₃).

Methyl 4-amino-6-methyl-1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3g). Yellowish solid. m.p. 190–192 °C. ¹H-NMR (DMSO) δ: 8.62–8.74 (m, 3H, Ar-H and pyrazole H), 8.37–8.40 (m, 2H, Ar-H), 7.84 (br, 2H, -NH₂), 3.92 (s, 3H, -OCH₃), 2.79 (s, 3H, -CH₃). ¹³C-NMR (DMSO) δ: 168.0, 161.4, 151.3, 150.9, 144.6, 136.6, 125.1, 119.8, 118.5, 105.0, 102.4, 51.8, 29.0. MS-ESI (m/z, relative intensity, %): 330 (M⁺+3) (3), 329 (M⁺+2) (18), 328 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,451, 3,330 (NH₂), 3,111 (ArH), 2,976, 2,926 (CH₃), 1,680 (C=O), 1,610, 1,543, 1,508 (C=N and aromatic ring skeleton vibration), 1,272 (O-CH₃).

Methyl 4-amino-1-(2,4-dinitrophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3h). Yellowish solid. m.p. 202–204 °C. ¹H-NMR (DMSO) δ: 8.86 (s, 1H, Ar-H), 8.69-8.73 (m, 1H, Ar-H), 8.52 (s, 1H, pyrazole H), 8.41–8.45 (m, 1H, Ar-H), 7.76 (br, 2H, -NH₂), 3.91 (s, 3H, -OCH₃), 2.80 (s, 3H, -CH₃). ¹³C-NMR (DMSO) δ: 167.8, 162.2, 151.4, 150.7, 137.4, 134.9, 128.6, 128.4, 126.3, 126.1, 126.0, 121.7, 119.5, 51.8, 28.2. MS-ESI (m/z, relative intensity, %): 375 (M⁺+3) (5), 374 (M⁺+2) (21), 373 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,332 (NH₂), 3,112 (ArH), 2,979, 2,933 (CH₃), 1,679 (C=O), 1,612, 1,550, 1,515 (C=N and aromatic ring skeleton vibration), 1,277 (O-CH₃).

Ethyl 4-amino-6-methyl-1-phenyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3i). Colorless solid. m.p. 130–131 °C. ¹H-NMR (CDCl₃) δ: 8.25 (d, J = 7.8 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.46–7.50 (m, 2H, Ar-H), 7.25–7.31 (m, 1H, Ar-H), 6.76 (br, 2H), 4.39 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.81 (s, 3H, -CH₃), 1.42 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 169.2, 162.5, 151.4, 150.2, 139.4, 131.7, 128.9, 126.1, 121.4, 105.1, 101.5, 60.7, 28.4, 14.3. MS-ESI (m/z, relative intensity, %): 299 (M⁺+3) (3), 298 (M⁺+2) (19), 297 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,333 (NH₂), 3,110 (ArH), 2,976, 2,926 (CH₂ and CH₃), 1,665 (C=O), 1,592, 1,494, 1,460 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Ethyl 4-amino-6-methyl-1-p-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3j). Colorless solid. m.p. 173–174 °C. ¹H-NMR (CDCl₃) δ: 8.09 (d, J = 6.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.25–7.29 (m, 2H, Ar-H), 6.72 (br, 2H, -NH₂), 4.40 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.81 (s, 3H, pyridine-CH₃), 2.39 (s, 3H, benzene-CH₃), 1.43 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 168.9, 162.0, 151.0, 149.7, 136.5, 135.5, 130.9, 129.1, 121.1, 104.5, 100.9, 60.3, 28.0, 20.6, 13.9. MS-ESI (m/z, relative intensity, %): 313 (M⁺+3) (2.5), 312 (M⁺+2) (22), 311 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,335 (NH₂), 3,112 (ArH), 2,977, 2,930 (CH₂ and CH₃), 1,658 (C=O), 1,590, 1,492, 1,460 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Ethyl 4-amino-6-methyl-1-m-tolyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3k). Colorless solid. m.p. 148–149 °C. ¹H-NMR (CDCl₃) δ: 8.08 (d, J = 8.7 Hz, 2H, Ar-H), 8.01 (s, 1H, pyrazole H), 7.38 (t, J = 7.8 Hz, 1H, Ar-H), 7.11 (d, J = 7.5 Hz, 1H, Ar-H), 6.72 (br, 2H, -NH₂), 4.40 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.82 (s, 3H, pyridine-CH₃), 2.45 (s, 3H, benzene-CH₃), 1.43 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 168.8, 162.1, 150.9, 149.6, 138.5, 131.1, 128.3, 126.6, 125.6, 121.7, 118.3, 104.6, 101.1, 60.4, 28.0, 21.2, 13.9. MS-ESI (m/z, relative intensity, %): 313 (M⁺+3) (2), 312 (M⁺+2) (20), 311 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,336 (NH₂), 3,111 (ArH), 2,976, 2,926 (CH₂ and CH₃), 1,662 (C=O), 1,590, 1,494, 1,462 (C=N and aromatic ring skeleton vibration), 1,262 (O-CH₃).

Ethyl 4-amino-1-(4-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3l). Colorless solid. m.p. 143–144 °C. ¹H-NMR (CDCl₃) δ: 8.27 (d, J = 6.6 Hz, 2H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.43–7.49 (m, 2H, Ar-H), 6.74 (br, 2H, -NH₂), 4.40 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.81 (s, 3H, -CH₃), 1.43 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 168.9, 162.0, 151.0, 135.3, 131.6, 130.9, 128.1, 121.1, 118.5, 104.5, 100.9, 60.3, 28.0, 13.9. MS-ESI (m/z, relative intensity, %): 334 (8), 333 (33), 331 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,338 (NH₂), 3,113 (ArH), 2,973, 2,925 (CH₂ and CH₃), 1,660 (C=O), 1,593, 1,457 (C=N and aromatic ring skeleton vibration), 1,260 (O-CH₃).

Ethyl 4-amino-1-(3-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3m). Colorless solid. m.p. 105–106 °C. ¹H-NMR (CDCl₃) δ: 8.37–8.42 (m, 1H, Ar-H), 8.28–8.33 (m, 1H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.41–7.46 (m, 1H, Ar-H), 7.23–7.27 (m, 1H, Ar-H), 6.73 (br, 2H, -NH₂), 4.41 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.83 (s, 3H, -CH₃), 1.44 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 168.7, 161.9, 150.9, 132.9, 131.6, 130.6, 130.2, 129.5, 128.6, 125.4, 121.8, 120.6, 118.5, 60.4, 27.9, 13.8. MS-ESI (m/z, relative intensity, %): 334 (6), 333 (31), 331 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,337 (NH₂), 3,111 (ArH), 2,974, 2,928 (CH₂ and CH₃), 1,661 (C=O), 1,592, 1,490, 1,458 (C=N and aromatic ring skeleton vibration), 1,258 (O-CH₃).

Ethyl 4-amino-1-(2-chlorophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3n). Colorless solid. m.p. 164–165 °C. ¹H-NMR (CDCl₃) δ: 8.11 (s, 1H, Ar-H), 8.04 (s, 1H, pyrazole H), 7.51–7.57 (m, 1H, Ar-H), 7.38–7.42 (m, 2H, Ar-H), 6.83 (br, 2H, -NH₂), 4.40 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.72 (s, 3H), 1.41 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (CDCl₃) δ: 168.8, 162.5, 151.1, 150.9, 135.4, 131.9, 131.8, 130.2, 129.6, 129.4, 126.9, 103.4, 101.2, 60.3, 27.7, 13.9. MS-ESI (m/z, relative intensity, %): 334 (5), 333 (32), 331 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,338 (NH₂), 3,112 (ArH), 2,973, 2,930 (CH₂ and CH₃), 1,660 (C=O), 1,590, 1,493, 1,457 (C=N and aromatic ring skeleton vibration), 1,263 (O-CH₃).

Ethyl 4-amino-6-methyl-1-(4-nitrophenyl)-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3o). Yellowish solid. m.p. 197–199 °C. ¹H-NMR (DMSO) δ: 8.62–8.74 (m, 3H, Ar-H and pyrazole H), 8.36–8.41 (m, 2H, Ar-H), 7.84 (br, 2H, -NH₂), 4.32 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.67 (s, 3H, -CH₃), 1.33 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (DMSO) δ: 167.8, 161.2, 151.0, 150.5, 144.4, 136.3, 124.9, 119.6, 118.9, 105.4, 102.6, 60.6, 29.3, 14.2. MS-ESI (m/z, relative intensity, %): 344 (M⁺+3) (2.5), 343 (M⁺+2) (18), 342 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,333 (NH₂), 3,112 (ArH), 2,978, 2,930 (CH₂ and CH₃), 1,678 (C=O), 1,616, 1,545, 1,512 (C=N and aromatic ring skeleton vibration), 1,275 (O-CH₃).

Ethyl 4-amino-1-(2,4-dinitrophenyl)-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carboxylate (3p). Yellowish solid. m.p. 205–206 °C. ¹H-NMR (DMSO) δ: 8.86 (s, 1H, Ar-H), 8.69–8.73 (m, 1H, Ar-H), 8.52 (s, 1H, pyrazole H), 8.43 (d, J = 9.0 Hz, 1H, Ar-H), 7.74 (br, 2H, -NH₂), 4.39 (q, J = 7.2 Hz, 2H, -CH₂CH₃), 2.66 (s, 3H, -CH₃), 1.39 (t, J = 7.2 Hz, 3H, -CH₂CH₃). ¹³C-NMR (DMSO) δ: 167.8, 162.2, 151.4, 150.7, 137.4, 134.9, 128.6, 128.4, 126.3, 126.1, 126.0, 121.7, 119.5, 60.2, 27.9, 14.0. MS-ESI (m/z, relative intensity, %): 389 (M⁺+3) (4), 388 (M⁺+2) (19), 387 (M⁺+1) (100). IR (KBr, cm⁻¹) ν: 3,453, 3,331 (NH₂), 3,113 (ArH), 2,979, 2,932 (CH₂ and CH₃), 1,680 (C=O), 1,617, 1,545, 1,512 (C=N and aromatic ring skeleton vibration), 1,272 (O-CH₃).

4. Conclusions

We have developed an efficient catalyst system using SnCl₄ in anhydrous toluene for the reaction between o-aminonitriles containing pyrazole moieties with β-ketoesters. A series of novel tacrine analogues 3a-p has been thus synthesized and their spectroscopic characterization and structural features have been presented.