HETEROCYCLES

Note | Regular issue | Vol. 78, No. 1, 2009, pp. 197-206
Received, 31st July, 2008, Accepted, 2nd September, 2008, Published online, 4th September, 2008.
DOI: 10.3987/COM-08-11510

■ A Novel and Efficient Approach to Pyrazolo[1,5-a]pyridine Derivatives via One-Pot Tandem Reaction

Yan-Qing Ge, Jiong Jia, Yan Li, Ling Yin, and Jianwu Wang*

School of Chemistry and Chemical Engineering, Shandong University, Jinan, 250100, China

Abstract

An unusual intramolecular condensation of α,β-unsaturated esters with aldehydes was discovered and the pyrazolo[1,5-a]pyridine derivatives were conveniently synthesized by this novel tandem reaction under very mild conditions. The reaction mechanism was also proposed.

The pyrazolo[1,5-a]pyridine derivatives have been of interest for their pharmacological and biological activities. They are used as dopamine D2, D3, D4 receptor antagonist, CRF1 receptor antagonist and nonxanthine adenosine A1 antagonist.1,2 They are also useful for the treatment of allergic diseases, herpes viral infection and the diseases mediated by MAPKAP-K2 such as inflammatory injury, autoimmune diseases, asteropathia destruens, cancer and growth of tumor.3,4
Synthetic approaches to pyrazolo[1,5-a]pyridine nucleus are under-represented in the literature.5 The general method for synthesis of pyrazolo[1,5-a]pyridine involves a [3+2] cyclic addition of N-aminopyridines with alkynoic esters.6 This strategy is limited in a number of ways. The low yield in the 1, 3-dipolar cycloaddition is problematic and not compatible with inexpensive synthesis. Besides, aminated pyridines have scarce substitutional availability from commercial sources.
Our previous work7 prompted us to find a novel method to synthesize the pyrazolo[1,5-a]pyridine derivatives. Herein an unusual intramolecular condensation of α,β-unsaturated esters with aldehydes was discovered, and the pyrazolo[1,5-a]pyridine derivatives were conveniently synthesized by a novel tandem reaction in mild conditions. The reaction mechanism was also proposed.

Pyrazoles 6a-f were prepared according to a literature method.8 The esters 6a-f were reduced to alcohols 7a-f with lithium aluminum hydride followed by oxidation with PCC to yield 1a-f (Scheme 1). It is well known that the β-carbon of α,β-unsaturated ester is an electrophilic center and can react with a variety of nucleophiles. The α-carbon of α,β-unsaturated ester is electron-rich relative to the β-carbon, but it is less known that α-carbon is nucleophilic and reacts with electrophiles.

We investigated the behavior of 1H-pyrazole-5-carbaldehyde 1 in a reaction with ethyl (E)-4-bromobut-2-enoate 2 in DMF in the presence of potassium carbonate at room temperature. The unexpected product was ethyl H-pyrazolo[1,5-a]pyridine-5-carboxylate 4a-l (Scheme 2).

When R2 was H or Me, the new annulated compounds 4a-l were obtained in moderate to good yields (65-82%) as stable solids. However, when R2 was Cl, we only obtained the products 3m-o under the same reaction conditions presumably because of the inductive effect. The results of the study are summarized in Table 1. In the light of products 3m-o, we envisioned that 3 should be the intermediate and could be synthesized through controlling the dosage of potassium carbonate or the reaction time. When 1 equivalent of potassium carbonate was used as a base, we could only get 3j independent of the reaction time used. While 2 or more equivalents of potassium carbonate were used, we could get 3j in 2 h, a mixture of 3j and 4j in 4 h and 4j in 6 h. The results are shown in Table 2. The 3j changed to 4j (isolated yield 88%) when we subjected it to 1 equivalent of potassium carbonate. Sodium hydroxide was also used as a base. We obtained a mixture of 3j and 4j 10 min later when 1 equivalent of sodium hydroxide was used and also obtained 4j (isolated yield 48%) in 1 h when 2 equivalents of sodium hydroxide were used.
The structures of adducts 3m-o and 4a-l were characterized by spectroscopic methods (1H and 13CNMR, IR, and MS). The structure of 4f was confirmed by X-ray crystallographic analysis as shown in Figure 1.

On the basis of the above results, we proposed the reaction mechanism as follows: Firstly, an intermolecular SN2 reaction between 1H-pyrazole-5-carbaldehyde 1 and ethyl (E)-4-bromobut-2-enoate 2 occurs, and the intermediate 3 is formed. Subsequently, intermediate 3 is deprotonated by the existing base to form a γ-carbanion of the ester, and in turn the electron pair transfers from the γ position to α position. Then the formed β,γ-unsaturated α-carbanion of ester (3’) cyclizes with the aldehyde group by intramolecular nucleophilic addition to afford intermediate 5. The final products 4 can be obtained in situ from 5 by eliminating water. The whole process is shown in Scheme 3.

In conclusion, we have described in this paper a novel tandem reaction to prepare pyrazolo[1,5-a]pyridine derivatives under mild conditions in good yields. The method can be useful to get access to this class of compounds. A reaction mechanism was also proposed. The compounds 4d, 4f, 4h are particularly interesting molecules due to their fluorescence (in both solution and solid state) and potential biological activity, which will be presented in due course.

EXPERIMENTAL
All reagents and solvents were purchased from Sinopharm Chemical Reagent Co. Ltd and used without further purification unless otherwise noted. Starting materials were prepared according to literatures. Thin-layer chromatography (TLC) was conducted on silica gel 60 F254 plates (Merck KGaA). 1H NMR spectra were recorded on a Bruker Avance 300 (300 MHz) spectrometer, using CDCl3 or DMSO-d6 as solvents and tetramethylsilane (TMS) as an internal standard. Melting points were determined on an XD-4 digital micro-melting point apparatus and are uncorrected. IR spectra were recorded with an IR spectrophotometer Avtar 370 FT-IR (Termo Nicolet). Elemental analyses were performed on a Vario EL III (Elementar Analysensysteme GmbH) spectroanalyzer. MS spectra were recorded on a Trace DSQ mass spectrometer.
General procedure for the synthesis and analytical data of 7a-f, 3j, 3m-o and 4a-l.
6a-e (1 mmol) was dissolved in THF and LAH (1 mmol) was added at 0 °C portionwise. The resulting mixture was stirred at the same temperature for 2 h and then allowed to warm to rt. The reaction was quenched by adding water before the mixture was partitioned between chloroform and water. The organic layer was separated and the aqueous layer was extracted with CHCl3. The combined organic layers were dried over anhydrous Na2SO4, and concentrated to afford 7a-f (yield: 81%-88%). To a 50-mL round-bottomed flask were added 7a-e (6.0 mmol), powdered pyridinium chlorochromate (2.59 g, 12 mmol) and DMF (10 mL). The mixture was stirred at rt for 3 h. After the staring material was consumed (monitored by TLC), the reaction mixture was poured into water (50 mL) and extracted with CH2Cl2 (3 × 20 mL). The combined organic extracts were washed with water (3 × 20 mL), dried over anhydrous MgSO4, filtered and concentrated in vacuo. The crude products 1a-e were used in the following step without further purification. To a 50-mL round-bottomed flask were added 1a-e (6.0 mmol), enoate 2a-c (7.2 mmol), potassium carbonate (1.60 g, 12.5 mmol) and DMF (10 mL). The mixture was stirred at rt for 2-8 h and then filtered. The filtrate was poured into water (50 mL) and extracted with CH2Cl2 (3 x 50 mL). The combined extracts were washed with water (2 x 50 mL), dried over anhydrous MgSO4 and filtered, and the solvent was removed by rotary evaporation. The crude products were purified by column chromatography.
Ethyl (Z)-3-chloro-4-(5-formyl-3-phenyl-1H-pyrazol-1-yl)but-2-enoate (3m)
Column chromatography (1:10 EtOAc: hexane) yielded a yellow oil. Yield: 86% 1H NMR (300 MHz, CDCl3): δ 9.90 (s, 1H), 7.36-7.84 (m, 5H), 7.26 (s, 1H), 6.29 (s, 1H), 6.09 (s, 2H), 4.28 (q, 2H, J = 7.2 Hz), 1.46 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 179.7, 164.0, 151.8, 148.6, 141.0, 131.8, 128.8, 128.6, 125.8, 121.7, 111.9, 61.1, 52.7, 14.2. IR (KBr) ν =3126, 3014, 2900, 2885, 1715, 1698, 1556, 1255, 1108, 758cm−1. Anal. Calcd for C16H15ClN2O3: C, 60.29; H, 4.74; N, 8.79. Found: C, 60.33; H, 4.75; N, 8.75.
Ethyl (Z)-3-chloro-4-(3-(4-chlorophenyl)-5-formyl-1H-pyrazol-1-yl)but-2-enoate (3n)
Column chromatography (1:10 EtOAc: hexane) yielded a yellow oil. Yield: 85% 1H NMR (300 MHz, CDCl3): δ 9.90 (s, 1H), 7.77 (d, 2H, J = 8.4 Hz), 7.39 (d, 2H, J = 8.4 Hz) 7.20 (s, 1H), 6.29 (s, 1H), 6.08 (s, 2H), 4.28 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 179.5, 163.9, 150.8, 148.3, 141.1, 134.4, 130.4, 129.0, 127.1, 121.8, 111.7, 61.1, 52.7, 14.2. IR (KBr) ν =3118, 3009, 2915, 2883, 1722, 1701, 1555, 1246, 1100, 762cm−1. Anal. Calcd for C16H14Cl2N2O3: C, 54.41; H, 4.00; N, 7.93. Found: C, 54.45; H, 4.01; N, 7.90.
Ethyl (Z)-3-chloro-4-(5-formyl-3-p-tolyl-1H-pyrazol-1-yl)but-2-enoate (3o)
Column chromatography (1:10 EtOAc: hexane) yielded a yellow oil. Yield: 88% 1H NMR (300 MHz, CDCl3): δ 9.89 (s, 1H), 7.72 (d, 2H, J = 8.4 Hz), 7.23 (d, 2H, J = 8.1 Hz) 7.19 (s, 1H), 6.28 (s, 1H), 6.07 (s, 2H), 4.27 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 179.0, 178.9, 163.3, 163.2, 151.2, 148.0, 147.9, 140.2, 140.1, 137.7, 128.7, 128.3, 128.2, 125.0, 120.9, 111.1, 111.0, 60.4, 52.0, 20.6, 13.5. IR (KBr) ν =3202, 3043, 2926, 2855, 1715, 1689, 1567, 1238, 1121, 785cm−1. Anal. Calcd for C17H17ClN2O3: C, 61.36; H, 5.15; N, 10.65. Found: C, 61.33; H, 5.13; N, 10.67.
Ethyl 4-(5-formyl-3-(p-tolyl)-1H-pyrazol-1-yl)-3-methylbut-2-enoate (3j)
Column chromatography (1:10 EtOAc: hexane) yielded a yellow oil. Yield: 70% 1H NMR (300 MHz, CDCl3) ( Z or E): δ 9.90 (s, 1H), 7.72 (d, 2H, J = 3.0 Hz), 7.25 (d, 2H, J = 3.0 Hz), 7.20 (s, 1H), 5.89 (s, 2H), 5.85 (s, 1H), 4.24 (q, 2H, J = 7.2 Hz), 1.35 (t, 3H, J = 7.2 Hz). (Z or E) δ 9.86 (s, 1H), 7.70 (d, 2H, J = 3.0 Hz), 7.22 (d, 2H, J =3.0 Hz) 7.20 (s, 1H), 5.20 (s, 2H), 5.25 (s, 1H), 4.10 (q, 2H, J =7.2 Hz), 1.23 (t, 3H, J =7.2 Hz). IR (KBr) ν =3134, 3013, 2936, 2832, 1725, 1704, 1604, 1559, 1248, 1115, 762cm−1. Anal. Calcd for C18H20N2O3: C, 69.21; H, 6.45; N, 8.97. Found: C, 69.22; H, 6.44; N, 8.99.
Ethyl 2-phenylpyrazolo[1,5-a]pyridine-5-carboxylate (4a)
White solid: mp 156-157 °C. 1H NMR (300 MHz, CDCl3): δ 8.78 (d, 1H, J =7.2Hz), 7.28 (dd, 1H, J = 7.2, 1.8 Hz), 8.36 (d, 1H, J = 1.8 Hz ), 7.37 (s, 1H), 8.00-8.02 (d, 2H), 7.42-7.53 (m, 3H), 4.36 (q, 2H, J = 7.2 Hz), 1.36 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 164.4, 153.9, 139.8, 131.9, 128.1, 127.5, 125.8, 124.9, 120.1, 110.2, 96.1, 60.9, 13.6. IR (KBr) ν =3120, 3054, 2973, 2898, 1712, 1529, 1506, 1473, 1455, 1296, 1268, 1254, 1192, 1100, 1083, 762, 753, 690cm−1. ESI-MS m/z Calcd: 266.3. Found: 267.3 [M++1]. Anal. Calcd for C16H14N2O2: C, 72.16; H, 5.30; N, 10.52. Found: C, 72.26; H, 5.32; N, 10.55.
Ethyl 6-methyl-2-phenylpyrazolo[1,5-a]pyridine-5-carboxylate (4b)
White solid: mp 118-119 °C. 1H NMR (300 MHz, CDCl3): δ 8.32 (s, 1H), 8.22 (s, 1H), 6.92 (s, 1H), 7.96 (d, 2H, J = 7.2 Hz), 7.38-7.48 (m, 3H), 4.40 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.55 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 165.3, 153.2, 138.6, 132.2, 128.1, 127.9, 126.9, 125.9, 125.7, 120.7, 120.5, 95.2, 60.6, 18.0, 13.6. IR (KBr) ν = 3121, 2984, 2973, 2928, 1716, 1520, 1471, 1445, 1313, 1262, 1253, 1220, 1183, 1150, 1087, 1051, 776, 767, 701 cm−1. ESI-MS m/z Calcd: 280.3. Found: 281.3 [M++1].
Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.96; H, 5.76; N, 9.93.
Ethyl 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4c)
White solid: mp 117-118 °C. 1H NMR (300 MHz, CDCl3): δ 8.49 (d, 1H, J = 7.5 Hz), 7.34 (dd, 1H, J = 7.5 Hz, 1.5 Hz), 8.29 (d, 1H, J = 1.8 Hz ), 6.95 (s, 1H), 7.95(m, 2H), 7.16 (m, 2H), 4.42 (q, 2H, J = 7.2 Hz), 1.44 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.1, 164.9, 153.7, 140.6, 128.9, 128.8, 128.3, 128.2, 128.1, 125.8, 120.8, 116.0, 115.7, 111.0, 96.5, 61.6, 14.3. IR (KBr) ν = 3123, 3051, 2990, 1710, 1600, 1516, 1475, 1270, 1231, 1192, 1101, 1026, 840, 783, 754, 519 cm−1. ESI-MS m/z Calcd: 284.3. Found: 285.3 [M++1]. Anal. Calcd for C16H13FN2O2: C, 67.60; H, 4.61; N, 9.85. Found: C, 67.71; H, 4.60; N, 9.89.
Ethyl 2-(4-fluorophenyl)-6-methylpyrazolo[1,5-a]pyridine-5-carboxylate (4d)
Green solid: mp 192-193 °C. 1H NMR (300 MHz, CDCl3): δ 8.30 (s, 1H), 8.21 (s, 1H), 6.86 (s, 1H), 7.92 (m, 2H), 7.15 (m, 2H), 4.40 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.55 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 165.9, 164.7, 161.5, 139.4, 129.2, 129.1, 128.2, 128.1, 127.6, 126.8, 121.3, 115.9, 115.6, 95.6, 61.3, 18.6, 14.3. IR (KBr) ν = 3062, 2980, 2925, 1722, 1606, 1517, 1477, 1448, 1312, 1269, 1232, 1082, 1050, 857, 845, 780, 527 cm−1. ESI-MS m/z Calcd: 298.3. Found: 299.3 [M++1]. Anal. Calcd for C17H15FN2O2 : C, 68.45; H, 5.07; N, 9.39. Found: C, 68.52; H, 5.08; N, 9.43.
Ethyl 2-(4-chlorophenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4e)
White solid: mp 184-185 °C. 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J = 7.2 Hz), 7.35 (dd, 1H, J = 7.2 Hz, 1.2 Hz), 8.30 (d, 1H, J = 1.2 Hz ), 6.97 (s, 1H), 7.90-7.93 (d, 2H, J = 7.2 Hz), 7.43-7.45 (d, 2H, J = 7.2 Hz), 4.44 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 164.3, 152.9, 139.9, 133.9, 130.4, 128.3, 128.1, 127.4, 127.0, 125.8, 125.1, 120.1, 110.4, 96.0, 60.9, 13.6. IR (KBr) ν = 3119, 3054, 2987, 2901, 1711, 1602, 1528, 1505, 1475, 1269, 1253, 1192, 1089, 1023, 784, 755 cm−1. ESI-MS m/z Calcd: 300.7. Found: 301.7 [M++1]. Anal. Calcd for C16H13ClN2O2: C, 63.90; H, 4.36; N, 9.31. Found: C, 63.99; H, 4.37; N, 9.33.
Ethyl 2-(4-chlorophenyl)-6-methylpyrazolo[1,5-a]pyridine-5-carboxylate (4f)
White solid: mp 133-134 °C. 1H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H), 8.21 (s, 1H), 6.89 (s, 1H), 7.89 (d, 2H, J = 8.4 Hz), 7.42 (d, 2H, J = 8.4 Hz), 4.41 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.55 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 165.2, 152.0, 138.7, 133.7, 130.7, 128.3, 127.0, 126.9, 126.2, 120.8, 120.6, 95.2, 60.6, 18.0, 13.6. IR (KBr) ν = 3138, 2981, 2929, 1725, 1520, 1473, 1446, 1407, 1312, 1261, 1222, 1187, 1150, 1083, 1053, 1021, 827, 782, 606 cm−1. ESI-MS m/z Calcd: 314.7. Found: 315.7 [M++1]. Anal. Calcd for C17H15ClN2O2: C, 64.87; H, 4.80; N, 8.90. Found: C, 64.91; H, 4.93; N, 8.94.
Ethyl 2-(4-bromophenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4g)
White solid: mp 175-177 °C. 1H NMR (300 MHz, CDCl3): δ 8.50 (d, 1H, J = 7.2 Hz), 7.37 (dd, 1H, J =
7.2 Hz, 1.8 Hz), 8.30 (d, 1H, J = 1.8 Hz), 6.98 (s, 1H), 7.85 (d, 2H, J = 8.7 Hz), 7.60 (d, 2H, J = 8.7 Hz),
4.42 (q, 2H, J = 7.2 Hz), 1.44 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 164.3, 152.8, 140.0, 131.3, 130.9, 128.1, 127.5, 127.3, 125.8, 125.1, 122.2, 120.1, 110.4, 96.0, 60.9, 13.6. IR (KBr) ν = 3117, 3053, 2984, 2900, 1712, 1596, 1527, 1505, 1474, 1362, 1270, 1253, 1191, 1102, 1023, 783, 754, 507 cm−1. ESI-MS m/z Calcd: 345.2. Found: 346.2 [M++1]. Anal. Calcd for C16H13BrN2O2: C, 55.67; H, 3.80; N, 8.12. Found: C, 55.74; H, 3.81; N, 8.14.
Ethyl 2-(4-bromophenyl)-6-methylpyrazolo[1,5-a]pyridine-5-carboxylate (4h)
Green solid: mp 157-158 °C. 1H NMR (300 MHz, CDCl3): δ 8.36 (s, 1H), 8.22 (s, 1H,), 6.91 (s, 1H), 7.83 (d, 2H, J = 8.4 Hz), 7.58 (d, 2H, J = 8.4 Hz), 4.40 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.56 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 165.9, 152.8, 139.4, 131.9, 131.8, 127.9, 127.6, 126.8, 122.6, 121.5, 121.4, 95.9, 61.3, 18.7, 14.3. IR (KBr) ν = 3134, 2978, 2927, 1724, 1612, 1519, 1471, 1457, 1445, 1404, 1311, 1260, 1220, 1186, 1152, 1084, 1020, 1009, 829, 780, 605, 506 cm−1. ESI-MS m/z Calcd: 359.2. Found: 359.2 [M++1]. Anal. Calcd for C17H15BrN2O2: C, 56.84; H, 4.21; N, 7.80. Found: C, 56.89; H, 4.21; N, 7.82.
Ethyl 2-(p-tolyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4i)
White solid: mp 158-159 °C. 1H NMR (300 MHz, CDCl3): δ 8.78 (d, 1H, J = 7.2 Hz), 7.26 (dd, 1H, J = 7.2 Hz, 1.8 Hz), 8.34 (d, 1H, J = 1.8 Hz ), 7.29 (s, 1H), 7.88-7.91 (d, 2H, J = 7.2 Hz), 7.30-7.32 (d, 2H, J = 7.2 Hz), 4.36 (q, 2H, J = 7.2 Hz), 1.36 (t, 3H, J = 7.2 Hz), 2.36 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 164.5, 153.9, 139.8, 138.0, 129.1, 128.8, 127.4, 125.7, 124.8, 120.0, 110.0, 95.8, 60.8, 20.7, 13.6. IR (KBr) ν = 3120, 3056, 2983, 1709, 1616, 1530, 1511, 1484, 1316, 1293, 1254, 1182, 1097, 1088, 1007, 825, 777, 758, 512 cm−1. ESI-MS m/z Calcd: 280.3 Found: 281.3 [M++1]. Anal. Calcd for C17H16N2O2: C, 72.84; H, 5.75; N, 9.99. Found: C, 72.93; H, 5.75; N, 9.95.
Ethyl 6-methyl-2-(p-tolyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4j)
White solid: mp 137-138 °C. 1H NMR (300 MHz, CDCl3): δ 8.31 (s, 1H), 8.20 (s, 1H), 6.89 (s, 1H), 7.85 (d, 2H, J = 8.1 Hz), 7.27 (d, 2H, J = 8.1 Hz), 4.39 (q, 2H, J = 7.2 Hz), 1.43 (t, 3H, J = 7.2 Hz), 2.55 (s, 3H), 2.40 (s, 3H). 13C NMR (75.4 MHz, CDCl3): δ 165.3, 153.3, 138.6, 137.8, 129.3, 128.8, 126.9, 125.8, 125.6, 120.6, 120.3, 95.0, 60.5, 20.6, 18.0, 13.6. IR (KBr) ν = 3130, 2979, 2928, 2902, 1708, 1615, 1517, 1477, 1447, 1403, 1310, 1263, 1148, 1088, 1023, 804, 510 cm−1. ESI-MS m/z Calcd: 294.3. Found: 295.3 [M++1]. Anal. Calcd for C18H18N2O2: C, 73.45; H, 6.16; N, 9.52; O, 10.87. Found: C, 73.52; H, 6.15; N, 9.50.
Ethyl 2-(4-methoxyphenyl)pyrazolo[1,5-a]pyridine-5-carboxylate (4k)
White solid: mp 144.5-145.5 °C. 1H NMR (300 MHz, CDCl3): δ 8.48 (d, 1H, J = 7.2 Hz), 8.27 (d, 1H, J = 1.8 Hz), 7.91 (d, 2H, J = 8.7Hz), 7.30 (dd, 1H, J = 7.2 Hz, 1.8 Hz), 7.00 (d, 2H, J = 8.7 Hz), 6.92 (s, 1H), 4.42 (q, 2H, J = 7.2 Hz), 3.87 (s, 3H), 1.43 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 165.2, 160.2, 154.5, 140.6, 128.1, 127.8, 125.6, 125.3, 120.6, 114.2, 110.5, 96.1, 61.5, 55.4, 14.3. IR (KBr) ν = 3116, 3053, 2980, 2957, 2837, 1718, 1614, 1514, 1478, 1305, 1270, 1253, 1180, 1101, 1035, 833, 778, 754 cm−1. ESI-MS m/z Calcd: 296.3. Found: 297.3 [M++1]. Anal. Calcd for C17H16N2O3: C, 68.91; H, 5.44; N, 9.45. Found: C, 68.97; H, 5.42; N, 9.48.
Ethyl 2-(4-methoxyphenyl)-6-methylpyrazolo[1,5-a]pyridine-5-carboxylate (4l)
White solid: mp 135-137 °C. 1H NMR (300 MHz, CDCl3): δ 8.34 (s, 1H), 8.20 (s, 1H), 7.90 (d, 2H, J = 8.7 Hz), 6.99 (d, 2H, J =8.7Hz), 6.84 (s, 1H), 4.40 (q, 2H, J = 7.2 Hz), 3.87 (s, 3H), 2.55 (s, 3H), 1.43 (t, 3H, J = 7.2 Hz). 13C NMR (75.4 MHz, CDCl3): δ 166.0, 160.1, 153.7, 139.3, 127.7, 127.6, 126.7, 125.4, 121.1, 121.0, 114.2, 95.2, 61.3, 55.4, 18.6, 14.3. IR (KBr) ν = 3121, 2975, 2929, 1718, 1610, 1521, 1477, 1459, 1439, 1312, 1244, 1177, 1082, 1026, 849, 782 cm−1. ESI-MS m/z Calcd: 296.3. Found: 297.3 [M++1]. Anal. Calcd for C18H18N2O3: C, 69.66; H, 5.85; N, 9.03; O, 15.47 Found: C, 69.71; H, 5.83; N, 9.07.

ACKNOWLEDGEMENTS
The authors thank the Shandong Natural Science Foundation (No. Y2008B40) and Shandong Excellent Young and Mid-aged Scientist Promotive Foundation (No. 2008BS04024) for financial support of this work. We also thank State Key Laboratory of Crystal Materials of Shandong University for crystal data.

References

1. I. Salama, C. Hocke, W. Utz, O. Prante, F. Boeckler, H. Huber, T. Kuwert, and P. Gmeiner, J. Med. Chem., 2007, 50, 489; CrossRef H. Lanig, W. Utz, and P. Gmeiner, J. Med. Chem., 2001, 44, 1151; CrossRef H. Huber and P. Gmeiner, Tetrahedron: Asymmetry, 2002, 13, 2303; CrossRef J. M. Fu, U.S. Patent 7 151 109, 2006.
2. S. Kuroda, A. Akahane, H. Itani, S. Nishimura, K. Durkin, T. Kinoshita, Y. Tenda, and K. Sakane, Bioorg. Med. Chem. Lett., 1999, 9, 1979; CrossRef S. Kuroda, A. Akahane, H. Itani, S. Nishimura, K. Durkin, T. Kinoshita, I. Nakanishi, and K. Sakane, Tetrahedron, 1999, 55, 10351; CrossRef A. Zanka, N. Hashimoto, R. Uematsu, and T. Okamoto, Org. Process Res. Dev., 1998, 2, 320; CrossRef S. Kuroda, A. Akahane, H. Itani, S. Nishimura, K. Durkin, Y. Tenda, and K. Sakane, Bioorg. Med. Chem., 2000, 8, 55. CrossRef
3. B. A. Johns, K. S. Gudmundsson, and S. H. Allen, Bioorg. Med. Chem. Lett., 2007, 17, 2858 and references cited therein. CrossRef
4. K. Gudmundsson and B. A. Johns, EP Patent 1 385 847, 2005; CrossRef K. L. Stevens, D. K. Jung, M. J. Alberti, J. G. Badiang, G. E. Peckham, J. M. Veal, M. Cheung, P. A. Harris, S. D. Chamberlain, and M. R. Peel, Org. Lett., 2005, 7, 4753. CrossRef
5. K. Kishore, K. R. Reddy, J. R. Suresh, H. Iia, and H. Junjappa, Tetrahedron, 1999, 55, 7645; CrossRef K.T. Potts, U. P. Singh, and J. Bhattacharyya, J. Org. Chem., 1968, 33, 3766; CrossRef E. Schweizer, J. E. Hayes, S. N. Hiewe, and A. L. Rheinggold, J. Org. Chem., 1987, 52, 1319; CrossRef Y. Miki, S. Yagi, H. Hachiken, and M. Ikeda, Heterocycles, 1994, 38, 1881; CrossRef D. Monguchi, S. Majumdars, and T. Kawabata, Heterocycles, 2006, 68, 2571. CrossRef
6. R. Huisgen, R. Grashey, P. Laur, and H. Leitermann, Angew. Chem., 1960, 72, 416; CrossRef V. Boekelheide and N. A. Fedoruk, J. Org. Chem., 1968, 33, 2062. CrossRef
7. J. W. Wang, J. Jia, D. J. Hou, H. M. li, and J. Yin, Chin. J. Org. Chem., 2003, 23, 173.
8. F. Wei, B. X. Zhao, B. Huang, L. Zhang, C. H. Sun, W. L. Dong, D. S. Shin, and J. Y. Miao, Bioorg. Med. Chem. Lett., 2006, 16, 6342 CrossRef