HETEROCYCLES

Short Paper | Regular issue | Vol. 87, No. 10, 2013, pp. 2081-2091
Received, 30th July, 2013, Accepted, 14th August, 2013, Published online, 22nd August, 2013.
DOI: 10.3987/COM-13-12793

■ EFFICIENT SYNTHESIS OF PURINE DERIVATIVES BY ONE-POT THREE-COMPONENT MANNICH TYPE REACTION

Qian Zhang,* Bai-Wei Ma, Yong-Zhen Huang, Qian-Qian Wang, Xing-Xing Wang, Gui-Rong Qu, and Hai-Ming Guo*

School of Chemical and Chemical Engineering, Henan Normal University, 46# East of Construction Road, Xinxiang, Henan 453007, China

Abstract

An efficient, facile three-component Mannich-type reaction on purine rings was described. This reaction proceeded smoothly under the catalysis of ethylenediamine at ambient temperature in high regioselectivities with exclusive N9-alkylated products. A wide range of purine derivatives were obtained in high yields.

Mannich-type reaction is one of the most useful reactions in organic synthesis due to the products including β-amino carbonyl motifs which are useful reaction intermediates.1 Many scientists devoted themselves to these researchs and compounds of kinds of different structures were obtained.2 Among them, one-pot three-component Mannich-type reactions which can give a wide range of structural variations have attracted wide attentions, and this structural diversity made the Mannich-type reaction more valuable.3
The discovery and wide application of acyclovir4 greatly stimulated the research interest in the synthesis of purine derivatives and searching new antiviral drugs.5 Penciclovir, famciclovir, and ganciclovir et al. were developed in succession and applied in clinic. There were many routes to obtain purine derivatives.
Alkylation,6 Michael addition7 and Mitsunobu reaction8 were commonly used ones. These methods often gave purine derivatives in high yields. However, Mannich-type reaction was less used in the preparation of purine derivatives.9
Herein we described the efficient synthesis of purine derivatives through one-pot three-component Mannich-type reactions with ethylenediamine as catalyst. The reaction finished at ambient temperature (15–20 °C) within 8 h, giving good to excellent isolated yields. The analogues of the products brought about by other kinds of reactions were obtained by two steps or four steps, which made yield low and work tedious.10
The optimization of reaction conditions was begun with studying the influence of catalysts on the three-component Mannich-type reaction with 6-chloro-9H-purine (1A), propionaldehyde (1B) and diethyl malonate (1C) in water at 15 °C. As shown in Table 1, the reaction does not occur without addition of a catalyst (entry 1). Many catalysts, including K2CO3, Cs2CO3, Na2HPO4∙12H2O, AcONa, AcOH and triethylamine (Table 1, entries 2–7) can hardly promote reactions at 15 °C. Further research showed that 50 mol% of ethylenediamine could catalyze reaction smoothly and gave desired product alone in 90% isolated yield (entries 8–15).
Continuously increasing or reducing the amount of ethylenediamine both led to decreased yields (entries 8–15). Temperature also had some effect on the yield of the product. The reaction proceeded successfully at 15–20 °C and gave single product with high isolated yields (entries 13, 16 and 17). Increasing temperature to 50 °C, the isolated yield gradually decreased because of the emergence of by-products (entries 18–20). Further screening of reaction time showed that the reaction can be completed within 8 h (entries 21–24). Therefore, we chose 50 mol% ethylenediamine as catalyst and the reactions were conducted at ambient temperature (15–20 °C) within 8 h.

To evaluate the general applicability and versatility of the method, a group of different purine derivatives and aliphatic aldehydes were subjected to the optimized reaction conditions and the results were shown in Table 2. As can be seen in Table 2, some of the purine substrates reacted ideally and gave high yields in water. Others can dissolve in water only partly or minimally, which resulted in poor reaction. When the solvents were changed into mixed solvent (H2O: DMF= 1:1) or DMSO, all the substrates gave desired products in high yields. We also investigated the influence of aliphatic aldehydes (entries 1, 15-18) and most of the aliphatic aldehydes reacted smoothly giving single products. Confusingly, when formaldehyde was used in the reaction, the conversion was very low.

The reaction gave high regioselectivities. As we know, the products of Mannich reaction of aliphatic aldehyde are prone to mixtures. Ethylenediamine can also be potentially involved in Mannich reaction. In our experiments, the single products were generated and ethylendiamine-related products were not found. The probable reason was that the reaction did not proceed by the classical Mannich path. That is, propionaldehyde and diethyl malonate interacted firstly to produce unsaturated ester in the presence of ethylenediamine, then Michael addition of purine with the unsaturated ester proceeded. Ethylenediamine took positive charge, which prevented ethylenediamine from reacting. In order to locate the side chain, the Heteronuclear Multiple-Bond Correlation (HMBC) spectroscopy of 1D was performed. As shown in Figure 1, C4 exhibited the 3J correlation with H1' (peak A) while C5 showed no correlation with protons in side chain, indicating that the side chain is located at N9 of purine.

In conclusion, we have developed a simple and efficient methodology for the preparation of purine derivatives by one-pot three-component Mannich-type reaction on purine rings. Compared with previously known approaches which contained more steps and not mild reaction conditions, this method catalyzed by ethylenediamine had only one step with which the reaction can proceed at ambient temperature. A number of functional groups can be tolerated.

EXPERIMENTAL
All reagents were purchased and used without further purification. Thin layer chromatography (TLC) was used to detect all reactions and 200-300 mesh silica gel was used as the stationary phase for column chromatography. Melting points were detected with a micro melting point apparatus and uncorrected. 1H NMR spectra were recorded on a Bruker Avance 400 MHz instrument. 13C NMR spectra were recorded on a Bruker Avance 100 MHz instrument. HMBC Spectroscopy was recorded on a Bruker Avance 400 MHz instrument. Chemical shifts (δ) were given in parts per million after calibration to residual isotopic solvent (CHCl3: δH = 7.26 ppm, δC = 77.0 ppm). Coupling constants (J) were given in hertz. electrospray ionization time-of-flight mass spectrometry (ESI-TOFMS) produced on a Bruker micrOTOF mss spectrometer. Infrared spectra were recorded in KBr with an Avatar360E. S. P. FTIR spectrophotometer.
General procedure for the reaction of 6-chloro-9H-purine (1A), propionaldehyde (1B) and diethyl malonate (1C)
6-Chloro-9H-purine (0.3 mmol), ethylenediamine (0.15 mmol), malonate (0.36 mmol), and propionaldehyde (0.36 mmol) were successively added to 1.5 mL water. This mixture was stirred at 15 °C for 8 h and extracted with EtOAc for three times. The organic layer was combined, dried with anhydrous Na2SO4 and evaporated to dryness. The crude mixture was purified by silica gel chromatography to give target product.
Diethyl 2-(1-(6-chloro-9H-purin-9-yl)propyl)malonate (1D): a white solid; mp 78–80 °C; IR (KBr disc) ν 3109, 3069, 2979, 2938, 2906, 2879, 1729, 1706 ,1590, 1562, 1492, 1439, 1369, 1336, 1209, 1144, 1095 cm-1; 1H NMR (400MHz, CDCl3): δ 8.75 (s, 1H), 8.23 (s,1H), 5.03 (t, J = 10.4 Hz, 1H), 4.45 (d, J = 9.8 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.09–3.87 (m, 2H), 2.54–2.34 (m, 1H), 2.23–1.77 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 166.5, 166.4, 151.7, 151.6, 151.2, 146.1, 131.9, 62.3, 62.1, 58.3, 55.3, 24.4, 13.9, 13.7, 10.6. HRMS (ESI) calcd. for C15H19ClN4O4 [M+H]+ 355.1168. Found: 355.1165.
Diethyl 2-(1-(2-amino-6-chloro-9H-purin-9-yl)propyl)malonate (2D): a white solid; mp 69–71 °C; IR (KBr disc) ν 3456, 3306, 3197, 2980, 2938, 1747, 1732, 1622, 1610, 1559, 1409, 1372, 1304, 1208, 1143, 1030 cm-1; 1H NMR (400MHz, CDCl3): δ 7.87 (s, 1H), 5.80 (s, 1H), 4.85 (td, J = 11.3, 3.4 Hz, 1H), 4.38 (d, J = 10.1 Hz, 1H), 4.28 (q, J = 7.1 Hz, 2H), 4.02 (t, J = 7.2 Hz, 2H), 2.30–2.38 (m, 1H), 1.89–1.94 (m 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.79 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3). δ 166.6, 166.4, 159.0, 153.6, 151.2, 142.9, 125.2, 62.2, 62.0, 57.4, 55.3, 24.2, 13.9, 13.7, 10.6. HRMS (ESI) calcd. for C15H20ClN5O4 [M+H]+ 370.1277. Found 370.1287.
Diethyl 2-(1-(2,6-dichloro-9H-purin-9-yl)propyl)malonate (3D): a white solid; mp 88–90 °C; IR (KBr disc) ν 3130, 2982, 2939, 1744, 1721, 1594, 1550, 1359, 1315, 1218, 1178, 1141 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.26 (s, 1H), 5.04–4.98 (m, 1H), 4.34 (d, J = 9.6 Hz, 1H), 4.29–4.24 (m, 2H), 4.08–3.99 (m, 2H), 2.39–2.30 (m, 1H), 2.06–2.00 (m, 1H), 1.31 (t, J = 7.1 Hz, 3H), 1.08 (t, J = 7.1 Hz, 3H), 0.81 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 166.3, 166.3, 152.9, 152.6, 151.7, 146.8, 130.9, 62.4, 62.1, 58.2, 55.1, 24.4, 13.9, 13.7, 10.6. HRMS (ESI) calcd. for C15H19Cl2N4O4 [M+H]+ 389.0778. Found 389.0777.
Diethyl 2-(1-(6-amino-9H-purin-9-yl)propyl)malonate (4D): a white solid; mp 144–146 °C; IR (KBr disc) ν 3433, 3330, 3212, 3119, 2972, 2937, 1739, 1712, 1652, 1600, 1474, 1365, 1333, 1293, 1214, 1181, 1089, 1023, 1000 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.33 (s, 1H), 7.82 (s, 1H), 5.95 (s, 2H), 4.89 (td, J = 11.3, 3.5 Hz, 1H), 4.47 (d, J = 10.1 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 3.99–3.92 (m, 2H), 2.44–2.36 (m, 1H), 1.95–1.89 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 166.8, 166.7, 155.6, 152.7, 149.9, 141.4, 120.0, 62.1, 61.9, 57.8, 55.5, 24.5, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C15H21N5O4 [M+H]+ 336.1666. Found 336.1666.
Diethyl 2-(1-(6-(bis(2-hydroxyethyl)amino)-9H-purin-9-yl)propyl)malonate (5D): a white solid; mp 210–212 °C; IR (KBr disc) ν 3352, 2976, 2877, 1747, 1731, 1585, 1480, 1369, 1336, 1217, 1037 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.29 (s, 1H), 7.83 (s, 1H), 4.90 (td, J = 11.3, 3.4 Hz, 1H), 4.49 (d, J = 9.9 Hz, 1H), 4.26 (q, J = 7.1 Hz, 2H), 4.24–3.83 (m, 10H), 2.53–2.30 (m, 1H), 1.97–1.81 (m, 1H), 1.30 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (100MHz, CDCl3) δ 166.8, 166.6, 156.9, 151.7, 150.6, 140.0, 120.1, 62.2, 61.9, 57.8, 55.3, 52.0, 24.2, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C19H29N5O6 [M+H]+ 424.2191. Found 424.2200.
Diethyl 2-(1-(6-(diethylamino)-9H-purin-9-yl)propyl)malonate (6D): a white solid; mp 219–221 °C; IR (KBr disc) ν 3114, 2976, 2934, 2877, 1751, 1736, 1586, 1563, 1520, 1479, 1370, 1284, 1030 cm-1; 1H NMR (400 MHz, CDCl3): δ 8.32 (s, 1H), 7.75 (s, 1H), 4.89 (td, J = 11.3, 3.2 Hz, 1H), 4.52 (d, J = 10.1 Hz, 1H), 4.28–4.23 (q, J = 9.8 Hz, 2H), 4.16–3.93 (m, 6H), 2.46–2.38 (m, 1H), 2.12–1.66 (m, 1H), 1.29 (t, J = 7.1 Hz, 9H), 1.00 (t, J = 7.1 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 166.7, 153.7, 152.2, 150.4, 139.0, 119.9, 62.0, 61.7, 57.5, 55.5, 43.0, 42.8, 24.3, 14.0, 13.6, 10.6. HRMS (ESI) calcd. for C19H29N5O4 [M+H]+ 392.2292. Found 392.2303.
Diethyl 2-(1-(6-iodo-9H-purin-9-yl)propyl)malonate (7D): a white solid. mp 102–104 °C; IR (KBr disc) ν 3110, 2975, 2937, 2791, 2695, 1731, 1737, 1643, 1584, 1004 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.62 (s, 1H), 8.19 (s, 1H), 5.01–4.94 (m, 1H), 4.43 (d, J = 9.8 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.04–3.90 (m, 2H), 2.47–2.39 (m, 1H), 2.02–1.96 (m, 1H), 1.29 (t, J = 7.1 Hz, 4H), 1.01 (t, J = 7.1 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.4, 151.7, 147.8, 145.4, 138.9, 122.3, 62.3, 62.1, 58.4, 55.3, 24.4, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C15H19IN4O4 [M+H]+ 447.0524. Found 447.0523.
Diethyl 2-(1-(2-chlro-6-(diethylamino)-9H-purin-9-yl)propyl)malonate (8D): a white solid. mp 63–65 °C; IR (KBr disc) ν 3115, 2977, 2936, 2877, 1750, 1733, 1584, 1462, 1321, 1097, 1030 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 4.86 (td, J = 11.2, 3.4 Hz, 1H), 4.40 (d, J = 9.8 Hz, 1H), 4.27–4.22 (q, J = 7.2, 2H), 4.18(s, 1H), 4.01 (q, J = 7.1 Hz, 2H), 3.73 (s, 2H), 2.52–2.25 (m, 1H), 1.95–1.89(m, 1H), 1.30 (t, J = 7.1 Hz, 9H), 1.05 (t, J = 7.1 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 166.6, 153.9, 153.5, 151.6, 139.3, 118.8, 62.1, 61.8, 57.4, 55.3, 43.6, 42.6, 24.3, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C19H28N5O4 [M+H]+ 426.1902. Found 426.1913.
Diethyl 2-(1-(2-chlro-6-bis-(t-Butyloxycarbonyl)-9H-purin-9-yl)propyl)malonate (9D): a white solid; mp 102–104 °C; IR (KBr disc) ν 3126, 2980, 2937, 1789, 1749, 1729, 1602, 1371, 1299, 1254. 1213, 1143, 1115 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.84 (s, 1H), 8.12 (s, 1H), 5.00 (td, J = 11.3, 3.6 Hz, 1H), 4.47 (d, J = 9.9 Hz, 1H), 4.25 (q, J = 7.1 Hz, 2H), 4.03–3.88 (m, 2H), 2.49–2.41 (m, 1H), 2.01–1.95 (m, 1H), 1.43 (s, 18H), 1.29 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.74 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.6, 166.4, 153.1, 151.7, 150.3, 145.5, 129.2, 83.6, 62.2, 61.9, 58.0, 55.4, 27.7, 24.3, 14.0, 13.7, 10.5. HRMS (ESI) calcd. for C25H37N5O8 [M+H]+ 536.2715. Found 536.2754.
Diethyl 2-(1-(6-(4-ethylpiperazin-1-yl)-9H-purin-9-yl)propyl)malonate (10D): a white solid; mp 78–80 °C; IR (KBr disc) ν 3109, 2973, 2936, 2887, 2809, 1737, 1732, 1585, 1566, 1476, 1332, 1003 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.28 (s, 1H), 7.72 (s, 1H), 4.85 (td, J = 11.2, 3.4 Hz, 1H), 4.45 (d, J = 10.0 Hz, 1H), 4.39–4.04 (m, 6H), 4.01–3.85 (m, 2H), 2.60–2.51 (m, 4H), 2.43 (q, J = 7.2 Hz, 2H), 2.40–2.27 (m, 1H), 1.92–1.83 (m, 1H), 1.24 (t, J = 7.1 Hz, 4H), 1.09 (t, J = 7.2 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H), 0.71 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 166.6, 153.8, 152.0, 150.8, 139.1, 120.3, 62.0, 61.8, 57.5, 55.4, 52.9, 52.4, 24.3, 14.0, 13.7, 11.9, 10.6. HRMS (ESI) calcd. for C21H32N6O4 [M+H]+ 433.2558. Found 433.2562.

Diethyl 2-(1-(6-(4-methylpiperazin-1-yl)-9H-purin-9-yl)propyl)malonate (11D): a white solid; mp 206–208 °C; IR (KBr disc) ν 3110, 2975, 2937, 2791, 2695, 1731, 1737, 1643, 1584, 1004 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.32 (s, 1H), 7.77 (s, 1H), 4.90 (td, J = 11.1, 3.2 Hz, 1H), 4.50 (d, J = 10.0 Hz, 1H), 4.41–4.15 (m, 6H), 4.04–3.92 (m, 2H), 2.55 (t, J = 4.9 Hz, 4H), 2.50–2.39 (m, 1H), 2.36 (s, 3H), 1.94–1.88 (m, 1H), 1.30 (d, J = 7.1 Hz, 3H), 1.02 (t, J = 7.1 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.9, 166.6, 153.8, 152.0, 150.8, 139.2, 120.3, 62.1, 61.8, 57.5, 55.4, 55.1, 46.2, 24.3, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C20H30N6O4 [M+H]+ 419.2401. Found 419.2396.
Diethyl 2-(1-(6-(piperidin-1-yl)-9H-purin-9-yl)propyl)malonate (12D): a white solid; mp 70–72 °C; IR (KBr disc) ν 3111, 2977, 2935, 2854, 1733, 1750, 1583, 1563, 1465, 1336, 1294, 1247, 1214, 1180, 1026 cm-1. 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 1H), 7.75 (s, 1H), 4.89 (td, J = 11.3, 3.3 Hz, 1H), 4.51 (d, J = 10.0 Hz, 1H), 4.27–4.22 (m, 6H), 4.03–3.91 (m, 2H), 2.47–2.33 (m, 1H), 1.94–1.86 (m, 1H), 1.75–1.64 (m, 6H), 1.29 (t, J = 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H), 0.76 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.0, 166.7, 153.8 , 152.1, 150.6, 138.8, 120.2, 62.0, 61.8, 57.5, 55.5, 26.1, 24.8, 24.4, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C20H29N5O4 [M+H]+ 404.2292. Found 404.2296.
Diethyl 2-(1-(2-chloro-6-(piperidin-1-yl)-9H-purin-9-yl)propyl)malonate (13D): a white solid; mp 124–126 °C; IR (KBr disc) ν 3121, 3022, 2977, 2938, 2867, 1742, 1720, 1586, 1468, 1309, 1270, 1211, 1112, 1026 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.74 (s, 1H), 4.86 (td, J = 11.2, 3.5 Hz, 1H), 4.71–3.74 (m, 9H), 2.47–2.29 (m, 1H), 1.95–1.83 (m, 1H), 1.71 (s, 6H), 1.29 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.77 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.8, 166.6, 153.8, 153.6, 151.9, 139.0, 118.9, 62.1, 61.8, 57.4, 55.3, 26.1, 24.6, 24.3, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C20H28ClN5O4 [M+H]+ 438.1903. Found 438.1920.
Diethyl 2-(1-(2-amino-6-(pyrrolidin-1-yl)-9H-purin-9-yl)propyl)malonate (14D): a white solid; mp 118–120 °C; IR (KBr disc) ν 3479, 3345, 3223, 2970, 2936, 2876, 1753, 1729, 1633, 1584, 1490, 1453, 1405, 1209, 1030 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 4.85 (s, 2H), 4.73 (td, J = 11.3, 3.3 Hz, 1H), 4.46 (d, J = 10.0 Hz, 1H), 4.24 (q, J = 7.1 Hz, 2H), 4.16–3.87 (m, 4H), 3.65 (s, 2H), 2.4–2.30 (m, 1H), 1.96 (s, 4H), 1.84–1.75 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H), 0.75 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 167.1, 166.8, 159.3, 153.5, 152.2, 137.1, 115.6, 61.9, 61.7, 56.9, 55.4, 24.0, 14.0, 13.7, 10.6. HRMS (ESI) calcd. for C19H28N6O4 [M+H]+ 405.2245. Found 405.2256.
Diethyl 2-(1-(6-chloro-9H-purin-9-yl)ethyl)malonate (15D): a white solid; mp 196–198 °C. IR (KBr disc) ν 3113, 3069, 2984, 2940, 2906, 1738, 1723, 1591, 1562, 1492, 1445, 1370, 1336, 1093 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.76 (s, 1H), 8.28 (s, 1H), 5.33 (dq, J = 9.4, 7.0 Hz, 1H), 4.44 (d, J = 9.5 Hz, 1H), 4.27 (q, J = 7.1 Hz, 2H), 4.10–3.94 (m, 2H), 1.84 (d, J = 7.0 Hz, 3H), 1.31 (t, J = 7.1 Hz, 3H), 1.05 (t, J = 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.4, 166.4, 151.6, 151.4, 151.0, 145.4, 132.0, 62.3, 62.1, 55.7, 52.0, 17.9, 14.0, 13.7. HRMS (ESI) calcd. for C14H17ClN4O4 [M+H]+ 341.1011. Found 341.1027.
Diethyl 2-(1-(6-chloro-9H-purin-9-yl)butyl)malonate (16D): a white solid, mp 69–71 °C; IR (KBr disc) ν 3110, 3069, 2964, 2936, 2875, 1732, 1737, 1591, 1561, 1471, 1442, 1370, 1337, 1339, 1200, 1097, 936 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.69 (s, 1H), 8.16 (s, 1H), 5.08 (td, J = 11.5, 3.3 Hz, 1H), 4.38 (d, J = 9.9 Hz, 1H), 4.21 (q, J = 7.1 Hz, 2H), 3.98–3.85 (m, 2H), 2.47–2.35 (m, 1H), 1.86–1.73 (m, 1H), 1.24 (t, J = 7.2 Hz, 3H), 1.16–1.05 (m, 1H), 0.95 (t, 7.1 Hz, 3H), 0.91–0.88 (m, 1H), 0.82 (t, J = 7.3 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.4, 151.7, 151.6, 151.1, 146.0, 131.9, 62.4, 62.1, 56.4, 55.4, 33.0, 19.2, 14.0, 13.7, 13.2. HRMS (ESI) calcd. for C16H21ClN4O4 [M+H]+ 369.1324. Found 369.1335.
Diethyl 2-(1-(6-chloro-9H-purin-9-yl)-2-methylpropyl)malonate (17D): a white solid; mp 190–192 °C; IR (KBr disc) ν 3115, 3067, 2976, 2938, 2877, 1749, 1733, 1589, 1558, 1437, 1395, 1372, 1336, 1203, 1028, 940 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.43 (s, 1H), 5.13 (t, J = 8.1 Hz, 1H), 4.44 (d, J = 8.5 Hz, 1H), 4.11 (q, J = 7.1 Hz, 2H), 4.07–4.01 (m, 2H), 2.56 (dq, J = 13.7, 6.8 Hz, 1H), 1.17 (t, J = 7.1 Hz, 3H), 1.08–0.96 (m, 6H), 0.84 (d, J = 6.7 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 166.5, 166.5, 152.5, 151.7, 151.0, 146.0, 131.1, 62.3, 62.1, 60.5, 53.6, 31.0, 20.1, 18.6, 13.8, 13.7. HRMS (ESI) calcd. for C16H21ClN4O4 [M+H]+ 369.1324. Found 369.1342.
Diethyl 2-((6-chloro-9H-purin-9-yl)methyl)malonate (18D): an oil; IR (KBr disc) ν 3112, 3068, 2968, 2875, 1746, 1730, 1590, 1437, 1390, 1372, 1337, 1201, 946 cm-1; 1H NMR (400 MHz, CDCl3) δ 8.75 (s, 1H), 8.20 (s, 1H), 4.79 (d, J = 7.2 Hz, 2H), 4.27–4.11 (m, 5H), 1.23 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 166.62, 152.10, 146.06, 62.48, 51.19, 42.47, 13.91. HRMS (ESI) calcd. for C13H15ClN4O4 [M+Na]+ 349.0674. Found 349.0669.

ACKNOWLEDGEMENTS
The authors thank the National Science Foundation of China (No. 21102038), The Program for Chang jiang Scholars and Innovative Research Team in University (IRT1061), The Program for Innovative Research Team in University of Henan Province (2012IRTSTHN006) and The Program for Henan Natural Science Research (2011B150019).

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