Synthesis and reactions of 2-pyrido-fused bicyclic compounds

Article abstract of DOI:10.3987/COM-14-12997

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

Full text of DOI:10.3987/COM-14-12997

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HETEROCYCLES, Vol. 89, No. 7, 2014
HETEROCYCLES, Vol. 89, No. 7, 2014, pp. 1594 - 1605. © 2014 The Japan Institute of Heterocyclic Chemistry
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, New Taipei City 24205,
Taiwan, ROC, 002181@mail.fju.edu.tw
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
SPh
SPh
Ts-N=C=O (3 equiv)
NaHCO3 (1 equiv)
hydroquinone (cat.)
R1
R2
SPh
R1
R2
R1
R2
acid or base
S
N
O
N
O
toluene, reflux
O2
Ts
3
Ts
2
1
Scheme 1. Synthesis of 4-(phenylthio)-5,6-dihydro-2-pyridones (3)
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

HETEROCYCLES, Vol. 89, No. 7, 2014
1595
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.
N
O
N
O
N
O
indolizinone
quinolizinone
pyridoazepinone
Figure 1. 2-Pyrido-fused bicyclic structures
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
SPh
SPh
Bu3SnH (2.2 equiv)
m-CPBA (6 equiv)
( )n
( )n
N
O
CH2Cl2, rt, 18 h
AIBN (0.6 equiv)
toluene, reflux, 2 h
N
H
O
Ts
3a, n = 1
3b, n = 2
3c, n = 3
4a, n = 1 (63%)
4b, n = 2 (62%)
4c, n = 3 (60%)
SO2Ph
t-BuOK (2 equiv)
THF, rt or reflux
N
O
( )n
( )n
N
H
O
OH
O
6a, n = 1 (58%)
6b, n = 2 (67%)
6c, n = 3 (53%)
5a, n = 1 (79%)
5b, n = 2 (84%)
5c, n = 3 (81%)
Scheme 2. Synthesis of 2-pyrido-fused bicyclic compounds 6

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HETEROCYCLES, Vol. 89, No. 7, 2014
oxidation of compounds 4 proceeded first at the thio group, followed by the reaction with the terminal
1
13
alkenyl group. The H and C 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.
SO2Ph
SO2Ph
SO2Ph
SO2Ph
B
H-B
t-BuOK
( )n
( )n
N
H
O
N
O
N
O
O
N
( )n
( )n
O
OH
O
O
5
A
B
C
SO2Ph
SO2Ph
SO2Ph
B
B
H
H-B
H-B
N
O
( )n
N
O
N
O
( )n
( )n
N
O
( )n
OH
OH
OH
OH
D
6
E
F
Scheme 3. Plausible mechanism for the formation of compounds 6 from compounds 5
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-a]azepines.21

HETEROCYCLES, Vol. 89, No. 7, 2014
1597
H
H2 (70 psi)
H
N
O
+
N
O
N
O
Pd/C (5 mol%)
MeOH, rt, 1 d
OH
OH
OH
8 (47%)
6b
7 (44%)
Scheme 4. Hydrogenation of compound 6b
Figure 2. X-Ray crystal structure of compound 8
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.

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HETEROCYCLES, Vol. 89, No. 7, 2014
H2
Pd
Pd

N
O
N
O
N
O
Pd/C

OH
OH
OH
6b
G
H
Pd
Pd
H2
H
H
+
N
O
N
O
+
N
O
N
O
Pd/C
OH
OH
OH
OH
I
J
7
8
Scheme 5. Plausible mechanism for the formation of products 7 and 8 from compounds 6b
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.
MsCl (3.2 equiv)
Et3N (3.2 equiv)
NaH (3 equiv)
N
O
N
O
N
O
THF, sealed tube
80 oC, 3 h
CH2Cl2, rt, 12 h
OMs
OH
10 (65%)
9 (88%)
6b
Scheme 6. Preparation of compound 10 from compound 6b
We have also carried out some synthetic transformations of compound 9 (Scheme 7). Reaction of
o
mesylate 9 with sodium cyanide in DMF at 120 C 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

HETEROCYCLES, Vol. 89, No. 7, 2014
1599
NaCN (4 equiv)
N
O
N
O
DMF, 120 oC, 6 h
CN
OMs
11 (61%)
9
NaN3 (4 equiv)
R
H
N
O
N
O
CuSO4 . 5H2O (5 mol%)
N
O
N
DMF, 120 oC, 6 h
N3
OMs
NaASC (10 mol%)
THF-H2O (1:1), 60 oC
N
9
12 (62%)
N
R
13a, R = Ph (90%)
13b, R = Bu (86%)
Scheme 7. Synthetic transformations of compound 9
N
O
N
H
N
N
Ph
Figure 3. HMBC correlations of compound 13a
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
1
13
with a Perkin Elmer 100 series FTIR spectrometer. H and C NMR spectra were mostly recorded on a
Bruker Avance 300 spectrometer operating at 300 and at 75 MHz, respectively. Chemical shifts () are
reported in parts per million (ppm) and the coupling constants (J) are given in Hertz. High resolution

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HETEROCYCLES, Vol. 89, No. 7, 2014
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,
o
60%) as a white solid; mp 150.1－152.4 C; 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)
o
To a solution of compound 4a (41 mg, 0.16 mmol) in CH2Cl2 (2 cm3) at 0 C 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－
o
111.9 C; 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－
o
123.0 C; 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

HETEROCYCLES, Vol. 89, No. 7, 2014
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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)
o
as eluent to give 6a (19.0 mg, 58%) as a white solid; mp 109.4－110.8 C; 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)
o
Found: M+, 183.1262. C10H17NO2 requires 183.1259. Compound 8: a white solid; mp 132.8－134.0 C;
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.

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HETEROCYCLES, Vol. 89, No. 7, 2014
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
o
heated in a sealed tube at 80 C 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)
o
as eluent to give 10 (20 mg, 65%) as a white solid; mp 96.4－97.8 C; 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.

HETEROCYCLES, Vol. 89, No. 7, 2014
1603
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
o
mmol) was then added via a syringe. The mixture was heated at 60 C 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,
o
0.196 mmol) was then added via a syringe. The mixture was heated at 60 C 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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