HETEROCYCLES

Paper | Regular issue | Vol. 87, No. 4, 2013, pp. 815-826
Received, 30th December, 2012, Accepted, 4th February, 2013, Published online, 20th February, 2013.
DOI: 10.3987/COM-12-12661

■ Synthesis of Nitrogen Bridgehead Heterocycles with Phosphonates via a Novel Tandem Process

Ya-Fei Xie, Yan-Qing Ge, Lei Feng, Hua-Qiang Xu, Song Meng, Gui-Long Zhao, Wei-Ren Xu, Jiong Jia,* and Jian-Wu Wang*

School of Chemistry and Chemical Engineering, Shandong University, 27 Shanda Nanlu, Jinan,Shandong, 250100, China

Abstract

A novel and efficient method was developed for the synthesis of nitrogen bridgehead heterocycles with phosphonates. Nitrogen containing five-membered heterocyclic aldehyde and diethy 3-bromoprop-1-enylphosphonate were used as substrates. Bridgehead nitrogen-containing arylphosphonates were obtained via one-pot reaction including four steps: SN2, deprotonation followed by electron flow, nucleophic additon and elimination of water.

INTRODUCTION
The importance of arylphosphonates in organic synthesis,1 materials,2 and medicinal chemistry3 has been well documented for years. They are used, e.g., in the synthesis of heterocyclic compounds,4 designing fuel cell membranes,5 materials with special optical properties,6 and building blocks in polymer sciences.7 There also has been a growing interest in these compounds in medicinal chemistry and nucleic acid chemistry due to biological activity such as inhibitors of farnesyl protein transferase,8 progesterone receptor antagonists3b and antiviral activity.9 Thus, the creation of new arylphosphonates could have a great impact on various fields of chemical science.10
Bridgehead nitrogen-containing heterocycles are an important class of compounds due to their presence in natural and non-natural products, which exhibit useful biological activities.11 Among such compounds, indolizine, pyrido[1,2-a]benzimidazole and pyrazolo[1,5-a]pyridine are particularly interesting because of their similarities and diversions in structure to indole.12 Synthetic indolizines can be used as calcium entry blockers,13 potential central nervous system depressants,14 5-HT3 receptor antagonist,15 histamine H3 receptor antagonists,16 cardiovascular agents,17 and PLA2 inhibitors.18 They have also drawn much attention owing to their possible usage as dyes and chemosensors.19 Pyrido[1,2-a]benzimidazoles receive much more attention because of their pharmaceutical applications as antifungal agents,20 antiviral agents21 and antineoplastic agents.22 Furthermore, some of them also exhibit unique fluorescent properties and potential application in electroluminescence (EL) materials.23 Pyrazolo[1,5-a]pyridines display numerous biological activities and pharmacological properties. For instance, some of them are used as dopamine D2-like receptor antagonist in the treatment of neurological disorders.24 Some derivatives are synthesized as adenosine A1 receptor antagonists25 and CRF1 receptor antagonist.26 Additionally, they are also useful for the treatment of rheumatoid arthritis27 and herpes viral infection.28
Despite continued interest in these building blocks, synthetic methods in the literatures suffer strict operation conditions or low yields.29 As far as we know, there remain no general synthetic routes to form these nitrogen bridgehead heterocycles.
Due to the synthetic and practical importance of arylphosphonate derivatives and bridgehead nitrogen-containing heterocycles, we are especially interested to extend the previously found tandem reaction30 to synthesize the nitrogen bridgehead heterocycles with phosphonate. Here, we report a convenient, transition metal-free and general method for the synthesis of indolizine, pyrido[1,2-a]benzimidazole and pyrazolo[1,5-a]pyridine phosphonates. Pyrrole-2-carbaldehyde (benzimidazole carbaldehyde or pyrazole carbaldehyde) and diethyl 3-bromoprop-1-enylphosphonate were used as substrates, potassium carbonate as the base, and DMF as the solvent in one-pot.

RESULTS AND DISCUSSION
The reaction conditions were optimized by using 4-propionyl-1H-pyrrole-2-carbaldehyde 1a and diethyl 3-bromoprop-1-enylphosphonate 2 as the model substrates, and K2CO3 in DMF was found to be the most efficient system (Table 1). It was started by screening various bases in DMF, and K2CO3 provided the highest yield (Table 1 entries 1-6). Then the effect of solvents was investigated, and DMF was proved to be the most efficient solvent (entries 7-11). The reaction was also carried out with NaH as the base and MeCN as the solvent, but yield of the product was much lower. Yields of 3a under other conditions were similar (entries 1, 3, 7, 11). Consequently, all following reactions were conducted with K2CO3 in DMF.
To explore the scope of this methodology, a variety of pyrrole-2-carbaldehyde were studied under the reaction conditions which were optimized above. As observed in Table 2, a series of indolizine phosphonates 3a-g were obtained in moderate to good yields under mild conditions. We tried aliphatic substituent ethyl and a variety of phenyl to investigate the effect of R1 on the yield. When R1 was 4-fluorophenyl, the lowest yield of 65% was obtained. When R1 was ethyl, 4-methoxyphenyl, 4-chlorophenyl or 4-nitrophenyl, we got analogously good yield, no matter the substituent attached to phenyl was electron-drawing or electron-donating. Thus, the yield was hardly dependent on the substituent R1.

The structures of adducts 3a-g were characterized by spectroscopic methods (1H and 13CNMR, IR, and MS). The structure of 3g was further confirmed by X-ray crystallographic analysis as shown in Figure 1.

On the basis of the structures of the products, we propose a plausible reaction course for the one-pot tandem reaction (Scheme 1). The first step is the formation of the intermediate A through an intermolecular SN2 reaction between pyrrole-2-carbaldehyde 1 and diethyl 3-bromoprop-1-enylphosphonate 2. The second step is initiated by deprotonation of the intermediate A, and then a series of electron flow makes the intermediate B formed. The third step is an intramolecular nucleophilic addition between the formed β,γ-unsaturated α-carbanion of ester and the aldehyde group, which afford intermediate C. In the fourth step, intramolecular Horner-Emmons type reaction does not occur under the condition, but the final product 3 is formed by elimination of one water molecule; the proposed reason is that the isolated product 3 is much more stable than the Horner-Emmons product 3’, due to the presence of conjugation between the aromatic ring and the P=O system.

To examine the applicability of the tandem reaction in synthesizing other nitrogen bridgehead heterocycles bearing phosphonate moiety, we also used benzo[d]imidazole-2-carbaldehyde and pyrazole-5-carbaldehyde as substrates.

As showed in Scheme 2, benzo[d]imidazole-2-carbaldehyde proceeded well under the same reaction conditions, and pyrido[1,2-a]benzimidazole phosphonates 5a, b were obtained in moderate yields.
When 1H-pyrazole-5-carbaldehyde 7 was treated with diethyl 3-bromoprop-1-enylphosphonate 2 under the similar reaction conditions, a complex mixture was obtained. But raising the reaction temperature to 70 °C produced a moderate yield (Scheme 3). We assume that, the two resonance structures (Scheme 4) result in different reactivity from other two reactants of pyrrole-2-carbaldehyde and benzo[d]imidazole-2-carbaldehyde. At low temperature, it is kinetically-controlled procedure. The different position of electronegativity on the pyrazole carbaldehyde nitrogens gives different reaction points in the first step, intermolecular SN2 reaction, in the proposed mechanism. This makes a complex mixcture resulted. At 70 °C, the reaction turns out to be thermodynamically controlled. Raising reaction temperature may be favourable for the effective intermediate I, which makes the reaction proceed as proposed reaction course.
In summary, we have demonstrated a novel tandem process which can be applied to the construction of nitrogen bridgehead heterocycles with phosphonates in moderate to good yields. Furthermore, the tandem reaction can be widely applied in synthesizing nitrogen bridgehead arylphosphonates including indolizine, pyrido[1,2-a]benzimidazole and pyrazolo[1,5-a]pyridine phosphonates. We believe that this method has great potential applications in nitrogen bridgehead arylphosphonates synthesis. Further efforts to investigate the reaction are ongoing in our group, and the results will be reported in the future.

EXPERIMENTAL
All reagents were commercially available and used without further purification unless otherwise noted. Starting materials were prepared according to literatures. Melting points were recorded on an XD-4digital micro melting point apparatus and uncorrected. 1H and 13C NMR spectra were recorded on a Bruker Avance 300 MHz spectrometer, using CDCl3 or DMSO-d6 as solvent and TMS as internal standard. 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. HRMS spectra were recorded on a Q-TOF6510 spectrograph (Agilent). Compounds 1a-g,31 4a-b,32 7a-c30a were prepared according to the literatures.
General procedure for the synthesis of diethyl 3-bromoprop-1-enylphosphonate 2
Compound 2 was synthesized according to the literature method (Scheme 5).33,34 To a 250-mL round-bottomed flask, triethyl phosphite (20 mL, 120 mmol) and allyl bromide (11 mL, 130 mmol) were added and the mixture was heated at 140 °C for 4 h. After evaporated under reduced pressure to remove the remaining ally bromide, the product, compound 9, was purified by column chromatography. Dry CH2Cl2 was added to dissolve compound 9, and the solution was cooled in an ice bath. Bromine (144 mmol) was added dropwise and the mixture was stirred for 2 h at rt. This mixture was poured into a saturated aqueous solution of Na2SO3, extracted with CH2Cl2 and dried over MgSO4. After evaporation of the solvent, compound 10 was obtained as a pale yellow oil, which was subjected to the following steps without purification. NaH (40 mmol, 60%) was dispersed in 30 mL dry CH2Cl2 and the solution was cooled in an ice bath. Diethyl 2,3-dibromopropylphosphonate 10 (30 mmol) in 20 mL dry CH2Cl2 was added dropwise and the mixture was stirred for 24 h at rt. The temperature was raised to reflux for additional 1 h. After filtrated over celite and evaporation of the solvent, pale yellow oil 2 was purified bycolumn chromatography in 40% yield.
General procedure for the synthesis and analytical data of 3a-g
The mixture of compound 1 (1.5 mmol), compound 2 (1.8 mmol), potassium carbonate (3.3 mmol) and 40 mL DMF was stirred at 40 °C for 6-8 h. When TLC indicated the end of reaction, the reaction mixture was poured to water (50 mL), and extracted by EtOAc (15 mL×3). The combined extracts were washed by brine and dried over anhydrous MgSO4. After concentrated under reduced pressure, the crude products were purified by column chromatography to afford 3a-g in 65-84% yield.
Diethyl 2-propionylindolizin-7-ylphosphonate (3a)
pale yellow solid; mp 102-104 °C. 1H NMR (CDCl3, 300 MHz): δ 1.24 (t, J = 7.4 Hz, 3H), 1.34 (t, J = 7.1 Hz, 6H), 2.95 (q, J = 7.3 Hz, 2H), 4.04-4.24 (m, 4H), 6.74-6.80 (m, 1H), 7.03 (s, 1H), 7.88 (s, 1H), 7.91 (dd, J = 3.0 Hz, J = 7.2 Hz, 1H), 8.00 (d, J = 16.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 8.4, 16.3, 16.4, 33.3, 62.27, 62.34, 103.5, 112.1, 112.2, 116.3, 116.6, 118.9, 125.3, 125.5, 127.6, 127.8, 129.2, 131.2, 131.5, 197.6; IR (KBr) ν = 3133, 3063, 2983, 2938, 2905, 1668, 1628, 1470, 1387, 1287, 1249, 1198, 1020, 965, 789 cm-1; ESI-MS m/z Calcd: 309.1. Found: 310.1 [M++1]. Anal. Calcd for C15H20NO4P: C, 58.25; H, 6.52; N, 4.53. Found: C, 58.27; H, 6.53; N, 4.55.
Diethyl 2-benzoylindolizin-7-ylphosphonate (3b)
brown solid; mp 103-105 °C. 1H NMR (CDCl3, 300 MHz): δ 1.35 (t, J = 7.1 Hz, 6H), 4.05-4.25 (m, 4H), 6.77-6.84 (m, 1H), 7.09 (s, 1H), 7.48-7.54 (m, 2H), 7.58-7.63 (m, 1H), 7.88-7.92 (m, 2H), 7.92-7.96 (m, 2H), 8.03 (d, J = 16.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.3, 62.4, 105.6, 112.2, 112.4, 116.6, 118.6, 119.2, 125.2, 125.4, 127.6, 127.8, 128.3, 128.4, 129.4, 131.1, 131.3, 132.2, 139.0, 191.4; IR (KBr) ν = 3138, 3060, 2981, 2941, 2900, 1641, 1470, 1318, 1240, 1024, 962, 795 cm-1; ESI-MS m/z Calcd: 357.1. Found: 358.1 [M++1]. Anal. Calcd for C19H20NO4P: C, 63.86; H, 5.64; N, 3.92. Found: C, 63.87; H, 5.64; N, 3.90.
Diethyl 2-(4-methylbenzoyl)indolizin-7-ylphosphonate (3c)
pale yellow-green solid; mp 132-134 °C. 1H NMR (CDCl3, 300 MHz): δ 1.35 (t, J = 7.1 Hz, 6H), 2.46 (s, 3H), 4.05-4.25 (m, 4H), 6.77-6.82 (m, 1H), 7.07 (s, 1H), 7.31 (d, J = 7.8 Hz, 2H), 7.84 (d, J = 7.8 Hz, 2H), 7.87 (s, 1H), 7.92-7.95 (m, 1H), 8.03 (d, J = 16.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 21.6, 62.3, 62.4, 105.6, 112.1, 112.3, 116.4, 118.5, 119.0, 125.2, 125.4, 127.6, 127.8, 128.5, 129.1, 129.6, 131.0, 131.3, 136.3, 143.0, 191.1; IR(KBr) ν = 3136, 3059, 2980, 2900, 1630, 1470, 1320, 1244, 1026, 969, 782 cm-1; ESI-MS m/z Calcd: 371.1. Found: 372.1 [M++1]. Anal. Calcd for C20H22NO4P: C, 64.68; H, 5.97; N, 3.77. Found: C, 64.66; H, 5.98; N, 3.77.
Diethyl 2-(4-methoxybenzoyl)indolizin-7-ylphosphonate (3d)
white solid; mp 167-169 °C. 1H NMR (CDCl3, 300 MHz): δ 1.35 (t, J = 7.1 Hz, 6H), 3.91 (s, 3H),4.05-4.25 (m, 4H), 6.77-6.83 (m, 1H), 6.98-7.02 (m, 2H), 7.06 (s, 1H), 7.87 (s, 1H), 7.92-7.99 (m, 3H), 8.03 (d, J = 16.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 55.5, 62.26, 62.33, 105.5, 112.0, 112.2, 113.7, 118.2, 118.9, 125.2, 125.4, 127.6, 127.7, 128.6, 130.9, 131.2, 131.6, 131.8, 163.1, 190.1; IR(KBr) ν = 3129, 2980, 2937, 2905, 1629, 1600, 1572, 1469, 1316, 1242, 1168, 1017, 953, 769 cm-1; ESI-MS m/z Calcd: 387.1. Found: 388.1 [M++1]. Anal. Calcd for C20H22NO5P: C, 62.01; H, 5.72; N, 3.62. Found: C, 62.03; H, 5.70; N, 3.59.
Diethyl 2-(4-chlorobenzoyl)indolizin-7-ylphosphonate (3e)
yellow-green solid; mp 136-138 °C. 1H NMR (CDCl3, 300 MHz): δ 1.35 (t, J = 7.1 Hz, 6H), 4.07-4.23 (m, 4H), 6.79-6.85 (m, 1H), 7.04 (s, 1H), 7.47-7.51 (m, 2H), 7.86-7.87 (m, 2H), 7.89-7.90 (m, 1H), 7.94 (dd, J = 7.1 Hz, J = 3.2 Hz, 1H), 8.03 (d, J = 16.5 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.3, 62.4, 105.5, 112.4, 112.5, 116.9, 118.4, 119.5, 125.2, 125.4, 127.6, 127.7, 127.9, 128.7, 128.9, 130.8, 130.9, 131.2, 131.4, 137.3, 138.7, 190.1; IR(KBr) ν = 3137, 2983, 2929, 1631, 1584, 1472, 1400, 1241, 1167, 1088, 1019, 954, 746 cm-1; ESI-MS m/z Calcd: 391.1. Found: 392.1 [M++1]. Anal. Calcd for C19H19ClNO4P: C, 58.25; H, 4.89; N, 3.58. Found: C, 58.26; H, 4.90; N, 3.59.
Diethyl 2-(4-fluorobenzoyl)indolizin-7-ylphosphonate (3f)
yellowish brown solid; mp 123-124 °C. 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, J = 7.1 Hz, 6H), 4.05-4.25 (m, 4H), 6.79-6.85 (m, 1H), 7.05 (s, 1H), 7.15-7.23 (m, 2H), 7.87 (s, 1H), 7.93-7.99 (m, 3H), 8.03 (d, J = 16.8 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.3, 62.4, 105.5, 112.3, 112.5, 115.4, 115.7, 118.4, 125.2, 125.4, 127.6, 127.7, 128.1, 131.1, 131.4, 131.9, 132.0, 135.17, 135.21, 163.6, 167.0, 189.9; IR(KBr) ν = 3136, 3064, 2983, 2939, 2901, 1640, 1594, 1504, 1470, 1387, 1318, 1240, 1155, 1082, 1024, 969, 886, 787 cm-1; ESI-MS m/z Calcd: 375.1. Found: 376.1 [M++1]. Anal. Calcd for C19H19FNO4P: C, 60.80; H, 5.10; N, 3.73. Found: C, 60.81; H, 5.08; N, 3.73.
Diethyl 2-(4-nitrobenzoyl)indolizin-7-ylphosphonate (3g)
yellow solid; mp 168-170 °C. 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, J = 7.1 Hz, 6H), 4.06-4.26 (m, 4H), 6.82-6.88 (m, 1H), 7.04 (s, 1H), 7.87 (s, 1H), 7.95 (dd, J = 7.2 Hz, J = 3.3 Hz, 1H), 8.01-8.07 (m, 3H), 8.36-8.38 (m, 2H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.36, 62.43, 105.3, 112.7, 112.9, 117.4, 118.7, 120.0, 123.6, 125.3, 125.5, 127.3, 127.6, 127.7, 130.1, 131.4, 131.6, 144.1, 149.8, 189.5; IR(KBr) ν = 3138, 2992, 1646, 1600, 1525, 1467, 1347, 1319, 1236, 1084, 1048, 1018, 961, 796 cm-1; ESI-MS m/z Calcd: 402.1. Found: 403.1 [M++1]. Anal. Calcd for C19H19N2O6P: C, 56.72; H, 4.76; N, 6.96. Found: C, 56.73; H, 4.77; N, 6.94.

General procedure for the synthesis and analytical data of 5a,b
Compounds 5a and 5b were obtained using the same method for 3a-g in 57%, 63% yields, respectively.
3-Diethoxyphosphorylpyrido[1,2-a]benzimidazole (5a)
yellow-green solid; mp 114-116 °C. 1H NMR (CDCl3, 300 MHz): δ 1.38 (t, J = 7.1 Hz, 6H), 4.12-4.31 (m, 4H), 7.16-7.22 (m, 1H), 7.45-7.50 (m, 1H), 7.58-7.64 (m, 1H), 7.96 (d, J = 8.1Hz,1H), 8.03 (d, J = 8.1 Hz, 1H), 8.26 (d, J = 17.1 Hz, 1H), 8.54-8.58 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.86, 62.93, 110.8, 120.5, 122.6, 123.3, 123.5, 125.2, 125.4, 126.6, 128.5; IR(KBr) ν = 3032, 2979, 2924, 1502, 1484, 1467, 1391, 1320, 1244, 1089, 1031, 966, 792, 757 cm-1; ESI-MS m/z Calcd: 304.1. Found: 305.1 [M++1]. Anal. Calcd for C15H17N2O3P: C, 59.21; H, 5.63; N, 9.21. Found: C, 59.19; H, 5.64; N, 9.19.
3-Diethoxyphosphoryl-7,8-dimethylpyrido[1,2-a]benzimidazole (5b)
yellow-green solid; mp 146-147 °C. 1H NMR (CDCl3, 300 MHz): δ 1.37 (t, J = 7.2 Hz, 6H), 2.48 (s, 3H), 2.50 (s, 3H), 4.10-4.33 (m, 4H), 7.07-7.13 (m, 1H), 7.67 (s, 1H), 7.75 (s, 1H), 8.16 (d, J = 16.8 Hz, 1H), 8.43-8.47 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 20.7, 20.8, 62.7, 62.8, 109.8, 110.0, 110.5, 120.3, 123.4, 123.6, 125.0, 125.2, 127.2, 127.3, 129.9, 132.3, 136.1, 143.9, 146.1, 146.3; IR(KBr) ν = 3047, 2985, 2942, 1503, 1467, 1388, 1297, 1249, 1081, 1023, 963, 841, 778 cm-1; ESI-MS m/z Calcd: 332.1. Found: 333.1 [M++1]. Anal. Calcd for C17H21N2O3P: C, 61.44; H, 6.37; N, 8.43. Found: C, 61.43; H, 6.36; N, 8.44.
General procedure for the synthesis and analytical data of 8a-c
To a 50-mL round-bottomed flask were added 6a-c (2.0 mmol), powdered pyridinium chlorochromate (0.86 g, 4 mmol) and DMF (10 mL). The mixture was stirred at rt for 3 h. Compound 2 (2.4 mmol) and potassium carbonate (4.4 mmol) were added when TLC indicated that compound 6a-c was all oxidized to 7a-c. The mixture was stirred at 70 °C for 8-12 h and then filtered. The filtrate was poured to water (50 mL) and extracted by EtOAc (15 mL×3). The combined extracts were washed by brine and then dried over anhydrous MgSO4. After concentrated under reduced pressure, the crude products were purified by column chromatography to afford 8a-c in 47-53% yield.
Diethyl 2-phenylpyrazolo[1,5-a]pyridin-5-ylphosphonate (8a)
white solid; mp 76-78 °C. 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, J = 7.1 Hz, 6H), 4.10-4.25 (m, 4H), 6.96-7.02 (m, 2H), 7.36-7.42 (m, 1H), 7.44-7.50 (m, 2H), 7.95-8.00 (m, 2H), 8.09-8.15 (m, 1H), 8.50-8.54 (m, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.5, 62.6, 96.2, 111.7, 111.8, 122.4, 124.0, 124.2, 125.0, 126.6, 128.4, 128.6, 128.8, 128.9, 132.6, 140.1, 140.4, 154.6; IR(KBr) ν = 3100, 3019, 2924, 2854, 1907, 1667, 1619, 1548, 1507, 1453, 1346, 1314, 1285, 1178, 1129, 1081, 997, 900, 784, 599 cm-1; ESI-MS m/z Calcd: 330.1. Found: 331.1 [M++1]. Anal. Calcd for C17H19N2O3P: C, 61.81; H, 5.80; N, 8.48. Found: C, 61.79; H, 5.81; N, 8.47.
Diethyl 2-p-tolylpyrazolo[1,5-a]pyridin-5-ylphosphonate (8b)
reddish oil, 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, J = 7.1Hz, 6H), 2.40 (s, 3H), 4.09-4.25 (m, 4H), 6.93-7.00 (m, 2H), 7.27 (d, J = 7.8 Hz, 2H), 7.86 (d, J = 7.8 Hz, 2H), 8.10 (d, J = 16.2 Hz, 1H), 8.51 (dd, J = 3.3 Hz, J = 6.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 21.3, 62.5, 62.6, 96.0, 111.5, 111.6, 122.2, 123.9, 124.1, 124.7, 126.5, 128.4, 128.6, 129.6, 129.8, 138.8, 140.1, 140.3, 154.7; IR(KBr) ν = 3110, 3028, 2976, 2924, 2858, 1924, 1725, 1620, 1546, 1518, 1462, 1338, 1284, 1244, 1091, 1019, 928, 784 cm-1; ESI-MS m/z Calcd: 344.1. Found: 345.1 [M++1]. Anal. Calcd for C18H21N2O3P: C, 62.78; H, 6.51; N, 8.14. Found: C, 62.80; H, 6.50; N, 8.14.
Diethyl 2-(4-fluorophenyl)pyrazolo[1,5-a]pyridin-5-ylphosphonate (8c)
white solid; mp 94-96 °C. 1H NMR (CDCl3, 300 MHz): δ 1.36 (t, J = 7.1 Hz, 6H), 4.07-4.25 (m, 4H), 6.91 (s, 1H), 6.96-7.02 (m, 1H), 7.12-7.18 (m, 2H), 7.92-7.97 (m, 2H), 8.11 (d, J = 16.2 Hz, 1H), 8.50 (dd, J = 3.0 Hz, J = 6.9 Hz, 1H); 13C NMR (CDCl3, 75 MHz): δ 16.3, 16.4, 62.5, 62.6, 95.9, 111.7, 111.9, 115.7, 116.0, 122.7, 124.0, 124.1, 125.3, 128.3, 128.4, 128.6, 128.85, 128.90, 140.2, 140.4, 153.6, 161.6, 164.9; IR(KBr) ν = 3077, 2984, 2935, 2905, 1890, 1603, 1474, 1255, 1157, 1097, 1027, 969, 811, 769, 586 cm-1; ESI-MS m/z Calcd: 348.1. Found: 349.1 [M++1]. Anal. Calcd for C17H18FN2O3P: C, 58.62; H, 5.21; N, 8.04. Found: C, 58.63; H, 5.21; N, 8.05.

ACKNOWLEDGEMENTS
The authors gratefully acknowledge the Science and Technology Special Major Project for Significant New Drugs Formulation (2011ZX09401-009), the Shandong Natural Science Foundation (NO. Y2008B40) and the Natural Science Foundation of Shandong Province (No. ZR2012BL04) for financial support of this work. We also thank State Key Laboratory of Crystal Materials of Shandong University for crystal data.

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