HETEROCYCLES

Paper | Regular issue | Vol. 89, No. 7, 2014, pp. 1594-1605
Received, 1st April, 2014, Accepted, 19th May, 2014, Published online, 20th May, 2014.
DOI: 10.3987/COM-14-12997

■ Synthesis and Reactions of 2-Pyrido-Fused Bicyclic Compounds

Shang-Shing P. Chou* and Yi-Ting Wu

Department of Chemistry, Fu Jen Catholic University, 510 Chung-Cheng Rd., Hsin-Chuang, New Taipei City 24205, Taiwan, R.O.C.

Abstract

Dihydropyridones derived from the aza-Diels–Alder reaction of 3-phenylthio-3-sulfolenes with p-toluenesulfonyl isocyanate (PTSI) gave readily the epoxy sulfones, which upon treatment with base afforded the 2-pyrido-fused bicyclic compounds. Some synthetic transformations of these compounds are also reported.

INTRODUCTION
Aza-Diels–Alder reactions are quite useful for constructing the piperidine derivatives.1 We have previously developed a new aza-Diels–Alder reaction,2 using thio-substituted 3-sulfolenes (1)3 to react with p-toluenesulfonyl isocyanate (PTSI) to give the cycloaddition products 2, which can be treated with acid or base to afford the 5,6-dihydro-2-pyridones 3 (Scheme 1). We have also used this method to prepare some indolizidines and quinolizidines,4 and other heterocyclic compounds.5 Some of these compounds showed novel biological activities.6

The 2-pyrido-fused bicyclic structures (Figure 1) comprise the skeleton of some natural products, such as the antitumor agent camptothecin7 and the alkaloid isosophoramine.8 There are many methods for synthesizing one or two such bicyclic structures,9–15 but very few methods have been developed for constructing all three such skeletons.16–18 We now report a new method for the synthesis of all these three systems of 2-pyrido-fused bicyclic compounds.

RESULTS AND DISCUSSION
Treatment of compounds 3a4, 3b2 and 3c with Bu3SnH/AIBN19 gave the secondary amides 4a–c, respectively (Scheme 2). Further oxidation of compounds 4a–c with m-CPBA (6 equiv) at room temperature led to the corresponding epoxy sulfones 5a–c in good yields. If less amounts of m-CPBA were used, a mixture of sulfoxides, sulfones and epoxy sulfones was obtained. This indicates that the

oxidation of compounds 4 proceeded first at the thio group, followed by the reaction with the terminal alkenyl group. The 1H and 13C NMR spectra of compounds 5a–c showed that compound 5a was a 1 : 1 diastereomeric mixture, whereas compounds 5b and 5c only existed as one diastereomer. It seems that the larger alkenyl groups present in compounds 5b and 5c make the epoxidation stereoselectively. Treatment of compounds 5a–c with t-BuOK in THF (at room temperature for 5b, and at reflux for 5a and 5c) gave the bicyclic products 6a–c, respectively.
A plausible mechanism for the formation of compounds 6 from compounds 5 by treatment with base is shown in Scheme 3. Deprotonation of compounds 5 by t-BuOK would generate the amide anions A, which can undergo intramolecular cyclization to give intermediates B. A series of protonation and deprotonation at equilibrium would then lead to intermediates F, which would undergo irreversible elimination of benzenesulfinic acid to give the stable bicyclic products 6.

Because some of the piperidine derivatives (including the bicyclic analogs) we previously made have shown novel biological activities,6 we have also carried out some synthetic transformations of compound 6b. Treatment of a solution of compound 6b in MeOH with atmospheric hydrogen at room temperature using Pd/C or PtO2 as the catalyst did not give any reaction. However, the reaction of compound 6b with hydrogen in a sealed bottle at 70 psi in the presence of 5 mol% of Pd/C gave the expected reduction product 7, together with the ring expansion product 8 (Scheme 4). The stereochemistry of compound 7 was determined by comparing with the spectral data of its trans diastereomer.16 The structure of compound 8 was established by X-ray crystallography (Figure 2),20 and has the interesting moiety of pyrido[1,2-α]azepines.21

A plausible mechanism for the formation of compounds 7 and 8 from hydrogenation of compound 6b is shown in Scheme 5. Hydrogenation of compound 6b would occur first at the C3-C4 double bond to give an intermediate G, which would then be converted to the palladium π-allyl complex H. Intramolecular cyclization would give generate a mixture of intermediates I and J, as shown in a similar case without the metal complex.16 Finally, hydrogenation at the C5-C6 double bond from the less hindered side would give the products 7 and 8.

Treatment of compound 6b with methanesulfonyl chloride (MsCl) in the presence of Et3N in CH2Cl2 gave the corresponding mesylate 9 in good yield (Scheme 6). Further reaction of compound 9 with NaH in THF at 80 oC gave the elimination product 10 with formation of the exocyclic double bond.

We have also carried out some synthetic transformations of compound 9 (Scheme 7). Reaction of mesylate 9 with sodium cyanide in DMF at 120 oC afforded the substitution product 11. Similarly, treatment of mesylate 9 with sodium azide provided the product 12. Compound 12 could further undergo the copper-catalyzed azide-alkyne cycloaddition (CuAAC) reaction22 with phenylacetylene and 1-hexyne in the presence of cupric sulfate and sodium ascorbate (NaASC) to give the triazoles 13a and 13b, respectively. The regiochemistry of compound 13a was established by the HMBC technique (Figure 3). Many triazoles have been made by the click chemistry,23 and have shown interesting biological activities.24

CONCLUSION
In summary, we have developed a new method for synthesizing all three classes (including the [6,5], [6,6], and [6,7] ring systems) of 2-pyrido-fused bicyclic compounds 6 from the epoxy sulfones 5, which are readily obtained from the aza-Diels–Alder reaction of 3-phenylthio-3-sulfolenes 1 with p-toluenesulfonyl isocyanate (PTSI). We have also studied some useful synthetic transformations of compound 6b.

EXPERIMENTAL
Melting points were determined with a SMP3 melting apparatus. Infrared spectra (ATR) were recorded with a Perkin Elmer 100 series FTIR spectrometer. 1H and 13C NMR spectra were mostly recorded on a Bruker Avance 300 spectrometer operating at 300 and at 75 MHz, respectively. Chemical shifts (δ) are reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution mass spectra (HRMS) were measured with a mass spectrometer Finnigan/Thermo Quest MAT 95XL. Flash column chromatographic purifications were performed using Merck 60 H silica gel.

6-(Hex-5-enyl)-4-(phenylthio)-5,6-dihydropyridin-2(1H)-one (4c)
To a refluxing solution of compound 3c (250 mg, 0.57 mmol) in degassed toluene (10 cm3) was added slowly a solution of Bu3SnH (0.33 cm3, 1.23 mmol) and AIBN (56 mg, 0.34 mmol) in toluene (20 cm3) over a period of 2 h. The solvent was then evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 1) containing 5% Et3N as eluent to give 4c (98 mg, 60%) as a white solid; mp 150.1－152.4 oC; νmax (film/cm-1) 3194, 3076, 2937, 1648, 1588, 1463, 1442, 1400, 1328, 1163, 1085, 1025, 911, 854, 750, 691; δH (300 MHz; CDCl3) 7.52－7.40 (5H, m), 5.85－5.71 (1H, m), 5.68 (1H, br s), 5.25 (1H, s), 5.03－4.95 (2H, m), 3.65－3.55 (1H, m), 2.51－2.31 (2H, m), 2.10－2.03 (2H, m), 1.66－1.52 (2H, m), 1.50－1.40 (4H, m); δC (75 MHz; CDCl3) 165.9, 155.2, 138.4, 135.5, 130.1, 129.9, 128.2, 114.9, 114.1, 51.0, 34.8, 34.7, 33.6, 28.6, 24.8. HRMS (EI) Found: M+, 287.1339. C17H21NOS requires 287.1344.

6-(3,4-Epoxybutyl)-4-(phenylsulfonyl)-5,6-dihydropyridin-2(1H)-one (5a)
To a solution of compound 4a (41 mg, 0.16 mmol) in CH2Cl2 (2 cm3) at 0 oC was added in portions of m-CPBA (70% in H2O, 220.2 mg, 0.96 mmol). The mixture was stirred at room temperature for 18 h, diluted with CH2Cl2 (30 cm3), and then sequentially washed with saturated sodium thiosulfate solution (15 cm3) and saturated sodium bicarbonate solution (15 cm3). The organic layer was dried (MgSO4), evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 2) containing 5% Et3N as eluent to give 5a (38.8 mg, 79%) as a white solid; mp 95.8－96.7 oC. The 1H and 13C NMR of compound 5a indicates that it is a 1 : 1 mixture of diastereomers. νmax (film/cm-1) 3241, 3064, 2930, 2858, 1671, 1623, 1554, 1447, 1330, 1161, 1086, 998, 964, 802, 730, 689; δH (300 MHz; CDCl3) 7.95 (2H, d, J = 7.2 Hz), 7.72 (1H, d, J = 7.2 Hz), 7.61 (2H, d, J = 7.2 Hz), 7.44 (0.5 H, br s), 7.29 (0.5 H, br s), 6.63 (1H, d, J = 0.9 Hz), 3.72－3.65 (1H, m), 2.86 (1H, dt, J = 6.6, 3.3 Hz), 2.76－2.63 (2H, m), 2.47－2.45 (1H, m), 2.34－2.23 (1H, m), 1.81－1.78 (3H, m), 1.44－1.28 (1H, m); δC (75 MHz; CDCl3) 164.2, 164.0, 150.6, 150.5, 137.0 (2×), 134.5 (2×), 129.6 (2×), 128.5 (2×), 127.3 (2×), 51.6, 51.4, 50.4, 50.2, 47.0, 46.8, 31.1, 30.9, 28.0, 27.7, 27.5 (2×). HRMS (ESI) Found: M+, 307.0867. C15H17NO4S requires 307.0878.

6-(4,5-Epoxypentyl)-4-(phenylsulfonyl)-5,6-dihydropyridin-2(1H)-one (5b)
A similar procedure as for compound 5a was used to give 5b (73 mg, 84%) as a white solid; mp 111.0－111.9 oC; νmax (film/cm-1) 3310, 3066, 2927, 1730, 1677, 1621, 1447, 1311, 1154, 1017, 998, 810, 757, 688; δH (300 MHz; CDCl3) 7.92－7.90 (2H, m), 7.74－7.69 (1H, m), 7.63－7.58 (2H, m), 6.62 (1H, s), 6.11 (1H, br s), 3.65－3.63 (1H, m), 2.89－2.77 (1H, m), 2.77－2.66 (2H, m), 2.45 (1H, dd, J = 4.8, 2.7 Hz), 2.33－2.28 (1H, m), 1.68－1.51 (6H, m); δC (75 MHz; CDCl3) 167.4, 137.7, 136.0, 134.2, 133.4, 129.6, 128.4, 53.8, 51.8, 46.9, 35.7, 31.9, 29.0, 21.2. HRMS (FAB) Found: M+, 321.1037. C16H19NO4S requires 321.1035.

6-(5,6-Epoxyhexyl)-4-(phenylsulfonyl)-5,6-dihydropyridin-2(1H)-one (5c)
A similar procedure as for compound 5a was used to give 5c (57 mg, 81%) as a white solid; mp 121.3－123.0 oC; νmax (film/cm-1) 3296, 2928, 1677, 1621, 1447, 1310, 1154, 1085, 729, 688; δH (300 MHz; CDCl3) 7.92－7.89 (2H, m), 7.71－7.69 (1H, m), 7.63－7.58 (2H, m), 6.73 (1H, br d, J = 7.5 Hz), 6.62 (1H, s), 3.63－3.59 (1H, m), 2.89－2.87 (1H, m), 2.77－2.64 (2H, m), 2.47－2.44 (1H, m), 2.25 (1H, dd, J = 17.1, 9.9 Hz), 1.61－1.28 (8H, m); δC (75 MHz; CDCl3) 164.1, 151.0, 137.1, 134.6, 129.7, 128.7, 127.4, 52.1, 50.9, 47.0, 34.6, 32.1, 27.7, 25.8, 24.9. HRMS (FAB) Found: M+, 335.1194. C17H21NO4S requires 335.1191.

3-(Hydroxymethyl)-2,3-dihydroindolizin-5(1H)-one (6a)
To a solution of compound 5a (60 mg, 0.20 mmol) in THF (10 cm3) at room temperature under N2 was added t-BuOK (22.4 mg, 0.40 mmol) in one portion. After refluxing for 3 h, the solvent was evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 1) as eluent to give 6a (19.0 mg, 58%) as a white solid; mp 109.4－110.8 oC; νmax (film/cm-1) 3332, 2961, 2926, 2854, 1650, 1557, 1459, 1438, 1311, 1260, 1158, 1139, 1086, 797; δH (300 MHz; CDCl3) 7.35 (1H, dd, J = 9.0, 6.9 Hz), 6.46 (1H, d, J = 9.0 Hz), 6.18 (1H, d, J = 6.9 Hz), 5.57 (1H, br s), 4.87－4.81 (1H, m), 3.89－3.86 (2H, m), 3.16－2.95 (2H, m), 2.39－2.29 (1H, m), 1.95－1.83 (1H, m); δC (125 MHz; CDCl3) 162.9, 152.4, 142.4, 116.3, 105.8, 66.7, 64.9, 30.8, 24.5. HRMS (ESI) Found: M+, 165.0780. C9H11NO2 requires 165.0790.

4-(Hydroxymethyl)-3,4-dihydro-1H-quinolizin-6(2H)-one (6b)
A similar procedure as for compound 6a was used to give 6b (47 mg, 67%) as a white solid; mp 116.4－118.2 oC; νmax (film/cm-1) 3329, 2928, 2857, 1649, 1615, 1552, 1450, 1369, 1261, 1160, 1143, 1064, 797; δH (300 MHz; CDCl3) 7.21 (1H, dd, J = 9.0, 6.9 Hz), 6.46 (1H, dd, J = 9.0, 0.9 Hz), 6.02 (1H, d, J = 6.9 Hz), 4.66 (1H, d, J = 13.8 Hz), 4.31－4.13 (1H, m), 4.07 (1H, br s), 3.93－3.71 (1H, m), 2.84－2.69 (2H, m), 2.08－1.93 (2H, m), 1.88－1.78 (1H, m), 1.68－1.59 (1H, m); δC (75 MHz; CDCl3) 164.2, 152.2, 139.5, 117.5, 106.0, 67.4, 49.2, 36.9, 34.1, 23.0. HRMS (FAB) Found: M+, 179.0949. C10H13NO2 requires 179.0946.

6-(Hydroxymethyl)-7,8,9,10-tetrahydropyrido[1,2-a]azepin-4(6H)-one (6c)
A similar procedure as for compound 6a was used to give 6c (50 mg, 53%) as a white solid; mp 122.8－124.0 oC; νmax (film/cm-1) 3331, 2951, 2853, 1651, 1625, 1552, 1450, 1330, 1262, 1161, 1140, 1069, 799; δH (300 MHz; CDCl3) 7.32 (1H, dd, J = 9.0, 6.9 Hz), 6.53 (1H, d, J = 9.0 Hz), 6.14 (1H, d, J = 6.9 Hz), 5.47 (1H, br s), 5.01－4.94 (1H, m), 4.31－4.01 (2H, m), 2.87－2.78 (1H, m), 2.74－2.64 (1H, m), 2.14－1.73 (3H, m), 1.60－1.48 (1H, m), 1.29－1.16 (2H, m); δC (75 MHz; CDCl3) 165.9, 152.1, 140.1, 117.6, 107.6, 72.9, 48.6, 33.9, 32.7, 32.1, 29.8. HRMS (EI) Found: M+, 193.1103. C11H15NO2 requires 193.1103.

cis-4-(Hydroxymethyl)-3,4,7,8,9,9a-hexahydro-1H-quinolizin-6(2H)-one (7) and cis-7-Hydroxy-1,2,3,7,8,9,10,10a-octahydropyrido[1,2-a]azepin-4(6H)-one (8)
To a solution of compound 6b (60 mg, 0.34 mmol) in methanol (2 cm3) in a pressure bottle was added Pd/C (2 mg, 0.02 mmol). Hydrogen gas was then filled to 70 psi, and the reaction was carried out at room temperature for 24 h. The reaction mixture was diluted with EtOAc, and was filtered through Celite. The solvent was evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 2) as eluent to give compound 7 (26 mg, 44%) and compound 8 (29 mg, 47%). Compound 7: a colorless liquid; νmax (neat/cm-1) 3404, 2936, 1622, 1614, 1416, 1338, 1284, 1160, 1055, 636; δH (300 MHz; CDCl3) 4.53 (1H, d, J = 5.1 Hz), 4.47 (1H, dd, J = 14.7, 2.4 Hz), 4.03 (1H, br s), 3.56－3.48 (1H, m), 2.94 (1H, dd, J = 14.7, 3.0 Hz), 2.44－2.40 (2H, m), 1.95－1.54 (9H, m), 1.45－1.36 (1H, m); δC (75 MHz; CDCl3) 173.6, 70.7, 59.5, 53.7, 36.5, 36.2, 31.6, 29.3, 19.4, 18.5. HRMS (FAB) Found: M+, 183.1262. C10H17NO2 requires 183.1259. Compound 8: a white solid; mp 132.8－134.0 oC; νmax (film/cm-1) 3372, 2936, 1616, 1472, 1343, 1055; δH (300 MHz; CDCl3) 4.27 (1H, dd, J = 13.0, 3.9 Hz), 3.92－3.86 (1H, br s), 3.66－3.59 (1H, m), 3.33－3.26 (1H, m), 2.68 (1H, dd, 13.0, 10.2 Hz), 2.44－2.21 (2H, m), 2.04－1.97 (1H, m), 1.91－1.42 (9H, m); δC (75 MHz; CDCl3) 170.9, 68.5, 57.9, 51.6, 36.9, 34.9, 32.0, 29.9, 19.3, 18.3. HRMS (FAB) Found: M+, 183.1259. C10H17NO2 requires 183.1259.

4-(Methanesulfonyloxy)-3,4-dihydro-1H-quinolizin-6(2H)-one (9)
To a solution of compound 7 (21.5 mg, 0.12 mmol) in CH2Cl2 (1 cm3) in an ice bath was added Et3N (59 µL, 0.42 mmol). Methanesulfonyl chloride (32 µL, 0.42 mmol) was then added dropwise. The reaction mixture was stirred at room temperature for 18 h. Sat. aq NaHCO3 (10 cm3) was added slowly, and the mixture was extracted with CH2Cl2 (2 × 10 cm3), dried (MgSO4), and evaporated under vacuum. The crude product was purified by flash chromatography using EtOAc–hexane (1 : 3) containing 5% Et3N as eluent to give 9 (27.0 mg, 88%) as a white solid; mp 112.4－113.8 oC; νmax (film/cm-1) 3015, 2936, 2864, 1661, 1583, 1554, 1467, 1429, 1350, 1241, 1173, 1085, 1070, 963, 909, 798, 692; δH (300 MHz; CDCl3) 7.23 (1H, dd, J = 9.0, 6.9 Hz), 6.44 (1H, d, J = 9.0 Hz), 6.01 (1H, d, J = 6.9 Hz), 4.74－4.70 (1H, m), 4.63－4.50 (2H, m), 3.19 (3H, s), 2.87－2.72 (2H, m), 2.19－2.00 (3H, m), 1.99－1.96 (1H, m); δC (75 MHz; CDCl3) 163.4, 150.9, 139.7, 117.9, 105.8, 76.7, 45.7, 38.5, 35.9, 33.6, 22.4. HRMS (FAB) Found: M+, 257.0726. C11H15NO4S requires 257.0722.

4-Methylene-3,4-dihydro-1H-quinolizin-6(2H)-one (10)
A solution of compound 9 (50 mg, 0.19 mmol) in THF (1.5 cm3) and NaH (28 mg, 0.57 mmol) was heated in a sealed tube at 80 oC for 3 h. After cooling to room temperature, the solvent was evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 4) as eluent to give 10 (20 mg, 65%) as a white solid; mp 96.4－97.8 oC; νmax (film/cm-1) 3052, 2930, 2861,1663, 1581, 1548, 1447, 1427, 1374, 1209, 1142, 1085, 1058, 969, 850, 798, 755; δH (300 MHz; CDCl3) 7.25 (1H, dd, J = 9.3, 8.4 Hz), 6.92 (1H, d, J = 8.4 Hz), 6.48 (1H, d, J = 9.3 Hz), 6.06 (1H, d, J = 6.6 Hz), 6.02－5.94 (1H, m), 2.65 (2H, t, J = 6.5 Hz), 2.20－2.04 (4H, m); δC (75 MHz; CDCl3) 163.1, 150.0, 139.6, 127.3, 123.8, 118.1, 105.9, 31.9, 30.0, 23.6. HRMS (EI) Found: M+, 161.0841. C10H11NO requires 161.0841.

4-(Cyanomethyl)-3,4-dihydro-1H-quinolizin-6(2H)-one (11)
A solution of compound 9 (90 mg, 0.35 mmol) and NaCN (69 mg, 1.4 mmol) in DMF (1.5 cm3) was heated at 120 oC for 6 h. After cooling to room temperature, CH2Cl2 (35 cm3) was added, and the reaction mixture was washed sequentially with water (10 cm3) and brine (10 cm3). The organic solution was dried (MgSO4), the solvent was evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 3) containing 5% Et3N as eluent to give 11 (40 mg, 61%) as a white solid; mp 110.8－111.3 oC; νmax (film/cm-1) 3434, 2917, 2247, 1647, 1618, 1544, 1462, 1261, 1163, 1094, 810, 739; δH (300 MHz; CDCl3) 7.42 (1H, dd, J = 9.3, 6.9 Hz), 6.44 (1H, d, J = 9.3 Hz), 6.11 (1H, d, J = 6.9 Hz), 3.10－3.05 (1H, m), 2.78 (2H, d, J = 6.6 Hz), 2.71－2.65 (2H, m), 2.07－1.81 (4H, m); δC (75 MHz; CDCl3) δ 163.9, 149.9, 139.5, 123.7, 118.2, 105.2, 55.7, 38.6, 31.4, 30.1, 23.8. HRMS (FAB) Found: M+, 188.0945. C11H12N2O requires 188.0950.

4-(Azidomethyl)-3,4-dihydro-1H-quinolizin-6(2H)-one (12)
A solution of compound 9 (90 mg, 0.35 mmol) and NaN3 (105 mg, 1.4 mmol) in DMF (1.5 cm3) was heated at 120 oC for 6 h. After cooling to room temperature, CH2Cl2 (35 cm3) was added, and the reaction mixture was washed sequentially with water (10 cm3) and brine (10 cm3). The organic solution was dried (MgSO4), the solvent was evaporated under vacuum, and the crude product was purified by flash chromatography using EtOAc–hexane (1 : 3) containing 5% Et3N as eluent to give 12 (44 mg, 62%) as a white solid; mp 99.8－101.3 oC; νmax (film/cm-1) 2922, 2851, 2102, 1661, 1586, 1552, 1466, 1428, 1325, 1255, 1142, 1104, 969, 795; δH (300 MHz; CDCl3) 7.22 (1H, dd, J = 9.0, 6.6 Hz), 6.47 (1H, d, J = 9.0 Hz), 5.97 (1H, d, J = 6.6 Hz), 4.64 (1H, d, J = 13.8 Hz), 4.31 (1H, dd, J = 13.8, 8.7 Hz), 3.71 (1H, d, J = 6.6 Hz), 2.84－2.70 (2H, m), 1.85－2.10 (3H, m), 1.73 (1H, dd, J = 8.1, 5.1 Hz); δC (75 MHz; CDCl3) 163.5, 151.1, 139.3, 118.1, 105.6, 58.2, 45.6, 34.2, 33.9, 23.1. HRMS (ESI) Found: M+, 204.0997. C10H12N4O requires 204.1011.

4-((4-Phenyl-1H-1,2,3-triazol-1-yl)methyl)-3,4-dihydro-1H-quinolizin-6(2H)-one (13a)
To a solution of compound 12 (8 mg, 0.04 mmol) in THF–H2O (1:1, 2 cm3) were added sodium ascorbate (NaASC, 1.6 mg, 0.008 mmol) and CuSO4·5H2O (1.0 mg, 0.004 mmol). Phenylacetylene (17.5 µL, 0.16 mmol) was then added via a syringe. The mixture was heated at 60 oC for 1 h. The solvent was evaporated under vacuum, and CH2Cl2 (20 cm3) was added. The organic solution was dried (MgSO4), and evaporated under vacuum. The crude product was purified by recrystallization from CH2Cl2 to give 13a (11 mg, 90%) as a white solid; mp 142.3－142.8 oC; νmax (film/cm-1) 3129, 3088, 2942, 2862, 1658, 1553, 1461, 1427, 1379, 1298, 1234, 1140, 1080, 952, 794, 767, 696; δH (300 MHz; CDCl3) 7.96 (1H, s), 7.85－7.82 (2H, m), 7.49－7.40 (2H, m), 7.34－7.27 (1H, m), 7.24 (1H, dd, J = 9.0, 6.6 Hz), 6.44 (1H, d, J = 9.0 Hz), 6.04 (1H, d, J = 6.6 Hz), 5.29 (1H, J = 14.1 Hz), 4.56－4.48 (1H, m), 4.34 (1H, dd, J = 14.1, 9.1 Hz), 3.04－2.82 (2H, m), 2.64－2.50 (1H, m), 2.43－2.39 (1H, m), 2.34－2.25 (1H, m), 1.79－1.67 (1H, m); δC (75 MHz; CDCl3) 163.4, 151.1, 147.8, 139.7, 130.5, 128.8 ,128.3, 125.8, 119.6, 118.2, 105.8, 58.8, 47.2, 35.0, 33.6, 24.4. HRMS (ESI) Found: M+, 306.1475. C18H18N4O requires 306.1481.

4-((4-Butyl-1H-1,2,3-triazol-1-yl)methyl)-3,4-dihydro-1H-quinolizin-6(2H)-one (13b)
To a solution of compound 12 (10 mg, 0.049 mmol) in THF–H2O (1:1, 2 cm3) were added sodium ascorbate (NaASC, 1.9 mg, 0.098 mmol) and CuSO4·5H2O (1.2 mg, 0.0049 mmol). 1-Hexyne (22.5 µL, 0.196 mmol) was then added via a syringe. The mixture was heated at 60 oC for 1 h. The solvent was evaporated under vacuum, and CH2Cl2 (20 cm3) was added. The organic solution was dried (MgSO4), and evaporated under vacuum. The crude product was purified by recrystallization from CH2Cl2 to give 13b (12 mg, 86%) as a white solid; mp 133.3－134.8 oC; νmax (film/cm-1) 3130, 2929, 2858, 1661, 1581, 1552, 1466, 1428, 1380, 1260, 1140, 1044, 953, 796, 731; δH (300 MHz; CDCl3) 7.42 (1H, s), 7.23 (1H, dd, J = 9.3, 6.6 Hz), 6.47 (1H, d, J = 9.3 Hz), 6.01 (1H, d, J = 6.6 Hz), 5.27 (1H, d, J = 13.8 Hz), 4.42－4.38 (1H, m), 4.25 (1H, dd, J = 13.8, 9.3 Hz), 2.98－2.89 (1H, m), 2.89－2.87 (1H, m), 2.72 (2H, t, J = 7.8 Hz), 2.56－2.51 (1H, m), 2.38－2.24 (2H, m), 1.71－1.66 (3H, m), 1.43－1.35 (2H, m), 0.94 (3H, t, J = 7.2 Hz); δC (75 MHz; CDCl3) 163.4, 151.1, 146.8, 139.7, 120.9, 118.2, 105.9, 58.8, 47.2, 34.9, 33.7, 31.5, 29.8, 29.2, 25.2, 24.3. HRMS (EI) Found: M+, 286.1792. C16H22N4O requires 286.1794.

ACKNOWLEDGEMENTS
Financial support of this work by the Ministry of Science and Technology of the Republic of China (NSC 97-2113-M-030-001-MY3 and NSC 101-2113-M-030-001-MY2) is gratefully acknowledged.

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