Synthesis of triazolyl-substituted quinolizidine imides

Article abstract of DOI:10.1002/jccs.201100610

Some bicyclic imides and triazole compounds have separately shown biological activities. We now combine these two structural features into the synthesis of triazolyl-substituted quinolizidine imides 21. Dihydro-2-pyridone compound 15, obtained previously

Full text of DOI:10.1002/jccs.201100610

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Article
Synthesis of Triazolyl-Substituted Quinolizidine Imides
Shang-Shing P. Chou,* Chang-Lin Lu and Yen-Hao Hsu
Department of Chemistry, Fu Jen Catholic University, Taipei, Taiwan 242, R.O.C.
(Received: Oct. 17, 2011; Accepted: Nov. 16, 2011; Published Online: Nov. 29, 2011; DOI: 10.1002/jccs.201100610)
Some bicyclic imides and triazole compounds have separately shown biological activities. We now com-
bine these two structural features into the synthesis of triazolyl-substituted quinolizidine imides 21.
Dihydro-2-pyridone compound 15, obtained previously from the aza-Diels-Alder reaction, was first oxi-
dized to the sulfone 16 which was effectively converted to the azide 17. Further click chemistry of com-
pound 17 with terminal alkynes provided regiospecifically the 1,4-disubstituted triazoles 18a-c. Sequen-
tial detosylation with Bu3SnH/AIBN, N-allylation and ring-closing metathesis (RCM) reaction then pro-
vided the bicyclic imides 21a-b.
Keywords: Aza-Diels-Alder reactions; Click chemistry; Dihydro-2-pyridones; Ring-closing metath-
esis (RCM); Quinolizidines; Imides.
INTRODUCTION
Scheme II Some biologically active cyclic imides
Many natural and synthetic compounds bearing the
piperidine ring often exhibit interesting biological activi-
ties.1 Various methods have been developed to synthesize
these compounds.2 The aza-Diels-Alder reaction is one of
the most versatile routes to construct the piperidine struc-
ture.3 We have previously reported that thio-substituted
3-sulfolenes 1 can undergo in situ thermal desulfonylation
and subsequent cycloaddition reaction with p-toluenesul-
fonyl isocyanate (PTSI) to give the cyclized products 2.
Further treatment with acid or base can yield the conju-
gated dihydro-2-pyridones 3 (Scheme I).4 We have re-
ported some synthetic applications of this method,5 and
have studied some of their biological activities.6
Sharpless as a set of modular reactions for the rapid synthe-
sis of combinatorial libraries especially through hetero-
atom links (C-X-C),12 and has been widely applied to drug
synthesis13 and materials science.14 Among these nearly
perfect “spring-loaded” reactions, probably the most widely
used reaction is the azide-alkyne cycloaddition catalyzed
by Cu(I) (abbreviated as CuAAC) giving the 1,4-disubsti-
tuted triazoles.15 We would like to report that we can com-
bine our aza-Diels-Alder reaction method and the click
chemistry to synthesize a series of triazolyl-substituted
quinolizidine imides, hopefully with unusual biological ac-
tivities.
Synthesis of 4-(phenylthio)-5,6-dihydro-2-
Scheme I
pyridones 3
It has been reported that cyclic imides such as mi-
grastatin,7 thalidomide,8 and julocrotine9 have very useful
biological activities. Some bicyclic imides including
rolziracetam10 and benzo-fused compounds 4 and 5 have
the potential for treating Alzheimer’s disease (Scheme
II).11
RESULTS AND DISCUSSION
Starting from 6-allyl-4-(phenylthio)-5,6-dihydro-2-
A new idea of “click chemistry” was introduced by
Dedicated to the memory of Professor Yung-Son Hon (1955–2011).
* Corresponding author. E-mail: chem1004@mails.fju.edu.tw
J. Chin. Chem. Soc. 2012, 59, 365-372
© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
365

Article
Chou et al.
pyridone (6),5a after experimenting some reaction condi-
tions, a fair yield of compound 7 was obtained by reacting
with acryloyl chloride in the presence of triethylamine and
a catalytic amount of 4-dimethylaminopyridine (DMAP) in
refluxing CH2Cl2. If NaH or BuLi was used as the base, the
yield of compound 7 was much lower. It seems that product
7 was rather easily decomposed by the strong base. Ring-
closing metathesis (RCM)16 of compound 7 with the Grubbs’
II catalyst in refluxing toluene afforded the bicyclic imide 8
in modest yield (Scheme III), together with the recovered
compound 7 (37%). Similar reaction of compound 7 with
the Grubbs’ I catalyst only gave the recovered starting ma-
terial.
Scheme IV Synthesis of bicyclic imide 10
mon organic solvents, which made purification of the prod-
ucts rather difficult.
Scheme III Synthesis of bicyclic imide 8
Scheme V Synthesis of azido bicyclic imides 13 and
14
The conversion of compound 6 to the N-acylated
product 9 was more successfully carried out by first react-
ing with BuLi at low temperature, followed by treatment
with methacryloyl chloride. The extra methyl group in
compound 9 probably made it less susceptible to nucleo-
philic attack by the strong base. Further RCM reaction of
compound 9 with Grubbs’ II catalyst provided a good
yield of the bicyclic imide 10 (Scheme IV). It was found
that both imides 8 and 10 were quite insoluble in ethyl ac-
etate.
Having encountered the above difficulties, we then
decided to carry out the click chemistry first and then to
form the bicyclic imide structure through RCM. Treatment
of compound 155a with mCPBA in CH2Cl2 provided the
sulfone 16 in excellent yield, which was reacted with so-
o
dium azide in DMF at 0 C to give the azide 17 in good
Compounds 8 and 10 were then oxidized with mCPBA
in CH2Cl2 to the corresponding sulfones 11 and 12 in excel-
lent yields. Further treatment of sulfones 11 and 12 with so-
dium azide in N,N-dimethylformamide (DMF) at 0 oC af-
forded the azides 13 and 14 in good yields, respectively
(Scheme V). However, we could not successfully react
compounds 13 and 14 with terminal alkynes either under
thermal reaction conditions17 or with Cu(I) catalysis at
room temperature.15 One possible reason was that the pre-
sumed cycloaddition product was not very soluble in com-
yield. Attempted reaction of compound 15 with NaN3 to
give the azide product 17 did not proceed at all. Apparently,
the electron-withdrawing sulfonyl group in compound 16
activates its reaction with NaN3. Further reaction of com-
pound 17 with the terminal alkynes in the presence of cu-
pric sulfate and sodium ascorbate (NaAsc) in THF/H2O
(1:1) at room temperature led to the expected triazole prod-
ucts 18a-c in fair to good yields. The regiochemistry of
compound 18a was proven by NOESY, which shows that
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CHEMICAL SOCIETY
Triazolyl-Substituted Quinolizidine Imides
the proton (d 8.09) on the triazole ring has significant
cross-signals with the H-3 (d 6.17) of the dihydro-2-pyri-
done. This result is also in agreement with the literature
findings about the regioselective formation of 1,4-disubsti-
tuted triazoles.15 Compounds 18a-c were treated with
Bu3SnH/AIBN18 to give the corresponding secondary
amides 19a-c in good yields. Deprotonation of compounds
19a-b with BuLi at -78 oC in THF in the presence of hexa-
methylphosphoric amide (HMPA), followed by reaction
with allyl bromide provided the N-allyl substituted prod-
ucts 20a-b in fair yields, respectively. However, similar re-
actions for compound 19c or the use of other bases (NaH or
LDA) did not lead to the expected N-allyl product. Appar-
ently, the ester group in compound 19c was not very stable
under these reaction conditions. It was found that the RCM
reaction of compounds 20a-b was successfully carried out
in the presence of Grubbs’I catalyst to give the bicyclic im-
ides 21a-b bearing the triazole structure in good yields, re-
spectively (Scheme VI).
will study the biological activities of products 21 and the
intermediates synthesized.
EXPERIMENTAL
General
Melting points were determined with a SMP3 melting
apparatus. Infrared spectra were recorded with a Perkin
Elmer 100 series FTIR spectrometer using the ATR (atten-
1
uated total reflectance) mode. H and 13C NMR spectra
were recorded on a Bruker Avance 300 or 800 spectrometer
operating at 300 or 800, and at 75 or 200 MHz, respectively
unless specified otherwise. Chemical shifts (d) 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. Elemental analyses were carried out
with Heraeus Vario III-NCSH, Heraeus CHN-O-S-Rapid
Analyzer or Elementar Vario EL III. Flash column chro-
matographic purifications were performed using Merck 60
H silica gel.
Synthesis of triazolyl-substituted quino-
lizidine imides
Acryloyl-6-allyl-4-(phenylthio)-5,6-dihydropyridin-
2(1H)-one (7)
Scheme VI
To a solution of compound 6 (200 mg, 0.8 mmol) and
DMAP (10 mg, 0.08 mmol) in CH2Cl2 (4 mL) at room tem-
perature under nitrogen were added sequentially with a sy-
ringe Et3N (0.57 mL, 4 mmol) and acryloyl chloride (0.21
mL, 2.4 mmol). The reaction mixture was refluxed for 24 h,
and then the solvent was removed under vacuum. Ethyl ac-
etate (20 mL) was added, and the organic solution was
washed with 5% HCl (20 mL), saturated NaHCO3 (20 mL)
and brine (20 mL), dried (MgSO4) and evaporated. The
crude product was purified by flash chromatography using
ethyl acetate/hexane (1:4-1:1) as eluent to give compound
o
7 (61.9 mg, 51%) as a white solid: mp 73.3-74.1 C (re-
cryst. CH2Cl2); IR (ATR) 3065, 2922, 2853, 1665, 1593,
1389, 1214 cm-1; 1H NMR (CDCl3) d 7.55-7.43 (5H, m),
6.98 (1H, dd, J = 16.8, 10.5 Hz), 6.35 (1H, dd, J = 16.8, 1.8
Hz), 5.83-5.73 (1H, m), 5.70 (1H, dd, J = 10.5, 1.8 Hz),
5.27 (1H, d, J = 2.4 Hz), 5.14-5.09 (2H, m), 4.86-4.79 (1H,
m), 2.82 (1H, ddd, J = 17.7, 6.0, 2.4 Hz), 2.50 (1H, dd, J =
17.7, 1.5 Hz), 2.46-2.33 (2H, m); 13C NMR (CDCl3) d
168.4, 163.4, 159.2, 135.5, 133.8, 131.7, 130.5, 130.1,
128.1, 127.7, 118.9, 114.5, 51.3, 36.7, 31.7; EI-MS (rela-
tive intensity) m/z 299 (M+, 2), 204 (28), 103 (10), 73 (28),
60 (28), 59 (100), 55 (15); Exact mass calcd for C17H17NO2S
m/z 299.0980, EI-HRMS m/z 299.0983. Anal. Calcd for
C17H17NO2S: C, 68.20; H, 5.72; N, 4.68. Found: C, 67.97;
In summary, we have successfully synthesized the
triazolyl-substituted quinolizidine imides 21a-b from the
dihydro-2-pyridone 15 in six steps, which include the acti-
vation of the 2-pyridone 16 with the phenylsulfonyl group,
substitution with sodium azide to give azide 17, click
chemistry to form the triazoles 18, detosylation with
Bu3SnH/AIBN, N-allylation and final RCM reaction. We
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Chou et al.
H, 5.70; N, 4.48.
313.1135.
2-(Phenylthio)-9,9a-dihydro-1H-quinolizine-4,6-dione
(8)
7-Methyl-2-(phenylthio)-9,9a-dihydro-1H-quinolizine-
4,6-dione (10)
A mixture of compound 7 (125 mg, 0.42 mmol) and
Grubbs’ II catalyst (17.7 mg, 0.021 mmol) in toluene (10
mL) was refluxed under nitrogen for 4 h. Another portion
of Grubbs’ II catalyst (17.7 mg, 0.021 mmol) was added,
and the reaction mixture was refluxed for 4 h. The solvent
was removed under vacuum, and the crude product was pu-
rified by flash chromatography using ethyl acetate/hexane
(1:1) as eluent to give compound 8 (51.7 mg, 57%) as a
white solid: mp 123 oC (decomp) (recryst. CH2Cl2/hexane);
IR (ATR) 3054, 2927, 2853, 1718, 1646, 1604, 1386, 1260
A mixture of compound 9 (250 mg, 0.8 mmol) and
Grubbs’ II catalyst (33.9 mg, 0.04 mmol) in toluene (16
mL) was refluxed under nitrogen for 8 h. The solvent was
removed under vacuum, and the crude product was purified
by flash chromatography using ethyl acetate/hexane (1:1)
as eluent to give compound 10 (188.4 mg, 83%) as a white
o
solid: mp 125 C (decomp) (recryst. CH2Cl2/hexane); IR
(ATR) 3044, 2945, 1702, 1609, 1392, 1262 cm-1; 1H NMR
(CDCl3) d 7.57-7.42 (5H, m), 6.42 (1H, br s), 5.40 (1H, d, J
= 2.1 Hz), 4.14-4.07 (1H, m), 2.69 (1H, ddd, J = 16.8, 12.3,
1
cm-1; H NMR (CDCl3) d 7.51-7.40 (5H, m), 6.71-6.65
2.1 Hz), 2.51-2.37 (3H, m), 1.91 (3H, d, J = 1.5 Hz); 13
C
(1H, m), 6.03 (1H, dd, J = 9.9, 2.1 Hz), 5.39 (1H, d, J = 1.8
Hz), 4.25-4.13 (1H, m), 2.72 (1H, ddd, J = 16.8, 12.6, 1.8
Hz), 2.58-2.39 (3H, m); 13C NMR (CDCl3) d 163.3, 162.5,
155.5, 139.6, 135.3, 130.4, 130.0, 127.1, 126.9, 115.9,
53.5, 35.3, 30.8; EI-MS (relative intensity) m/z 271 (M+,
70), 204 (52), 176 (65), 148 (45), 147 (55), 109 (63), 77
(70), 71 (42), 69 (50), 68 (44), 67 (100), 65 (54), 57 (91),
55 (87), 51 (47); Exact mass calcd for C15H13NO2S m/z
271.0667, EI-HRMS m/z 271.0660.
NMR (CDCl3) d 164.6, 162.8, 155.3, 135.4, 133.8, 133.6,
130.4, 130.1,127.4, 116.3, 53.6, 35.6, 30.5, 17.2; EI-MS
(relative intensity) m/z 285 (M+, 2), 88 (11), 86 (66), 84
(100), 51 (29); Exact mass calcd for C16H15NO2S m/z
285.0823, EI-HRMS m/z 285.0820. Anal. Calcd for
C16H15NO2S: C, 67.34; H, 5.30; N, 4.91. Found: C, 67.35;
H, 5.06; N, 4.90.
General procedure for oxidation with mCPBA
To a solution of the sulfide (0.13 mmol) in CH2Cl2 (2
mL) in an ice bath was added mCPBA (70-75% in H2O,
0.325 mmol). After 5 min the ice bath was removed, and
the mixture was further stirred at room temperature for 2 h.
The reaction mixture was then added successively satu-
rated Na2S2O3 (10 mL) and saturated NaHCO3 (10 mL),
and was extracted with CH2Cl2 (20 mL). The organic solu-
tion was dried over K2CO3 and evaporated. The crude
product was recrystallized from CH2Cl2/hexane to give the
purified sulfone products.
6-Allyl-1-(2-methylacryloyl)-4-(phenylthio)-5,6-di-
hydropyridin-2(1H)-one (9)
To a solution of compound 6 (200 mg, 0.8 mmol) in
o
THF (5 mL) at -78 C under nitrogen was added slowly
with a syringe BuLi (0.42 mL, 2.5 M, 1.04 mmol). After
stirring for 30 min, methacryloyl chloride (0.33 mL, 3.2
mmol) was added in one portion. The reaction mixture was
slowly warmed to room temperature, and the solvent was
removed under vacuum. Ethyl acetate (20 mL) was added,
and the organic solution was washed with 5% HCl (20 mL),
saturated NaHCO3 (20 mL) and brine (20 mL), dried
(MgSO4) and evaporated. The crude product was purified
by flash chromatography using ethyl acetate/hexane (1:6-
1:1) as eluent to give compound 9 (179.5 mg, 70%) as a
white solid: mp 63.2-65.0 oC (recryst. CH2Cl2); IR (ATR)
3075, 2923, 1679, 1656, 1591, 1335 cm-1; 1H NMR (CDCl3)
d 7.55-7.42 (5H, m), 5.85-5.72 (1H, m), 5.35 (1H, d, J = 2.4
Hz), 5.16-5.09 (4H, m), 4.63-4.56 (1H, m), 2.84 (1H, ddd,
2-(Phenylsulfonyl)-9,9a-dihydro-1H-quinolizine-4,6-
dione (11)
o
White solid; mp 124 C (decomp) (recryst. CH2Cl2/
hexane); IR (ATR) 3070, 2925, 1726, 1664, 1447, 1392,
1264, 1151 cm-1; 1H NMR (CDCl3) d 7.92-7.89 (2H, m),
7.77-7.72 (1H, m), 7.69-7.56 (2H, m), 6.77-6.71 (1H, m),
6.68 (1H, d, J = 2.7 Hz), 6.03 (1H, dd, J = 9.9, 2.4 Hz),
4.27-4.16 (1H, m), 2.85 (1H, dd, J = 17.4, 4.5 Hz), 2.63-
2.44 (3H, m); 13C NMR (CDCl3) d 162.7, 161.8, 150.0,
141.0, 136.7, 134.9, 129.9, 128.7, 128.4, 126.3, 54.0, 30.9,
28.8; Exact mass calcd for C15H14NO4S m/z 304.0644
(M++H), ESI-HRMS m/z 304.0644 (M++H).
J = 17.4, 6.0, 2.4 Hz), 2.55-2.30 (3H, m), 1.95 (3H, s); 13
C
NMR (CDCl3) d 174.3, 162.9, 159.0, 142.9, 135.4, 133.8,
130.5, 130.0, 127.6, 118.9, 116.4, 114.2, 52.0, 36.6, 31.7,
19.2; EI-MS (relative intensity) m/z 313 (M+, 30), 312 (21),
272 (25), 204 (15), 69 (100), 109 (63), 67 (13); Exact mass
calcd for C18H19NO2S m/z 313.1136, EI-HRMS m/z
7-Methyl-2-(phenylsulfonyl)-9,9a-dihydro-1H-quino-
lizine-4,6-dione (12)
o
White solid; mp 139 C (decomp) (recryst. CH2Cl2/
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CHEMICAL SOCIETY
Triazolyl-Substituted Quinolizidine Imides
hexane); IR (ATR) 3087, 2964, 1717, 1436, 1394, 1287,
1156 cm-1; 1H NMR (CDCl3) d 7.92-7.89 (2H, m), 7.77-
7.72 (1H, m), 7.65-7.60 (2H, m), 6.68 (1H, d, J = 5.7 Hz),
6.49-6.47 (1H, m), 4.20-4.09 (1H, m), 2.84 (1H, dd, J =
17.1, 4.2 Hz), 2.50-2.39 (3H, m), 1.90 (3H, d, J = 1.5 Hz);
13C NMR (CDCl3) d 164.1, 162.0, 150.0, 136.7, 135.4,
134.8, 132.9, 129.8, 128.6, 128.5, 53.9, 30.5, 28.9, 17.1;
FAB-MS (relative intensity) m/z 318 (M++H, 85), 110 (30),
77 (31), 69 (36), 57 (36), 55 (52), 43 (40), 41 (45), 39
(100); Exact mass calcd for C16H15NO4S m/z 317.0722,
FAB-HRMS m/z 317.0728.
J = 17.1, 12.3, 2.1 Hz), 2.52-2.38 (2H, m), 2.34 (1H, dd, J =
17.1, 4.5 Hz), 1.93 (3H, d, J = 1.8 Hz); 13C NMR (CDCl3) d
164.6, 163.9, 152.2, 133.8 (´2), 109.4, 52.9, 33.3, 30.6,
17.2; Exact mass calcd for C10H10N4NaO2 m/z 241.0701
(M++Na), ESI-HRMS m/z 241.0698 (M++Na).
6-Allyl-4-azido-1-tosyl-5,6-dihydropyridin-2(1H)-one
(17)
Orange oil; IR (ATR) 3073, 2109, 1676, 1620, 1166
1
cm-1; H NMR (CDCl3) d 7.95 (2H, d, J = 8.4 Hz), 7.31
(2H, d, J = 8.4 Hz), 5.82-5.71 (1H, m), 5.52 (1H, d, J = 2.3
Hz), 5.19-5.09 (2H, m), 4.90-4.83 (1H, m), 2.82 (1H, ddd,
J = 17.4, 6.3, 2.3 Hz), 2.63-2.36 (6H, m); 13C NMR
(CDCl3) d 162.1, 153.6, 144.9, 136.6, 133.0, 129.4, 129.1,
119.9, 107.2, 53.4, 38.1, 29.8, 21.7; EI-MS (relative inten-
sity) m/z 333 (M++H, 39), 332 (M+, 3), 217 (14), 201 (10),
171 (25), 155 (59), 108 (12), 107 (12), 92 (10), 91 (100), 65
(19); Exact mass calcd for C15H16N4O3S m/z 332.0943,
EI-HRMS m/z 332.0952.
6-Allyl-4-(phenylsulfonyl)-1-tosyl-5,6-dihydropyridin-
2(1H)-one (16)
o
White solid; mp 163.4-164.6 C (recryst. CH2Cl2/
hexane); IR (ATR) 3068, 2926, 1710, 1692, 1639, 1596,
1320, 1154 cm-1; 1H NMR (CDCl3) d 7.95-7.87 (4H, m),
7.75-7.70 (1H, m), 7.64-7.59 (2H, m), 7.29 (2H, d, J = 8.4
Hz), 6.62 (1H, d, J = 2.4 Hz), 5.57-5.43 (1H, m), 4.98 (1H,
d, J = 10.2 Hz), 4.89-4.82 (1H, m), 4.67 (1H, d, J = 17.1
Hz), 2.75-2.66 (2H, m), 2.48-2.42 (4H, m), 2.18-2.10 (1H,
m); 13C NMR (CDCl3) d 160.3, 151.6, 145.5, 136.5, 135.6,
134.9, 131.9, 129.9, 129.5, 129.2, 128.9, 127.0, 120.3,
54.4, 37.9, 26.1, 21.7; Exact mass calcd for C21H22NO5S2
m/z 432.0939 (M++H), ESI-HRMS m/z 432.0945.
General procedure for the reaction of sulfones with
sodium azide
General procedure for the reaction of azide 17 with
alkynes
To a solution of azide 17 (0.28 mmol), CuSO4·5H2O
(0.014 mmol) and NaAsc (0.028 mmol) in THF/H2O (1:1, 2
mL) was added with a syringe the alkyne (0.56 mmol). The
reaction mixture was stirred at room temperature for 12 h,
and was evaporated under vacuum. The crude product was
purified by flash chromatography using ethyl acetate/hex-
ane (1:4-1:3) and 5% Et3N as eluent to give purified product.
6-Allyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-1-tosyl-5,6-
dihydropyridin-2(1H)-one (18a)
White solid; mp 185.0-186.2 oC (recryst. CH2Cl2); IR
(ATR) 3144, 2924, 2846, 1683, 1647, 1352, 1225, 1162,
1018 cm-1; 1H NMR (CDCl3) d 8.19 (1H, s), 7.98 (2H, d, J =
8.4 Hz), 7.89-7.86 (2H, m), 7.48-7.35 (3H, m), 7.30 (2H, d,
J = 8.4 Hz), 6.22 (1H, d, J = 2.6 Hz), 5.87-5.73 (1H, m),
5.17-5.02 (3H, m), 3.76 (1H, dd, J = 18.3, 0.9 Hz), 3.24
(1H, ddd, J = 18.3, 6.6, 2.6 Hz), 2.65-2.48 (2H, m), 2.48
(3H, s); 13C NMR (CDCl3) d 162.0, 149.2, 145.7, 145.1,
136.2, 132.5, 129.4, 129.2, 129.08 (´2), 129.02, 126.1,
120.2, 116.8, 108.8, 53.7, 38.4, 28.3, 28.2, 21.7; Exact
mass calcd for C23H23N4O3S m/z 435.1491 (M++H),
ESI-HRMS m/z 435.1487 (M++H).
To a solution of the sulfone (0.11 mmol) in DMF (1
mL) in an ice bath was added NaN3 (0.22 mmol). After stir-
ring for 30 min, ethyl acetate (20 mL) was added. The or-
ganic solution was washed sequentially with water (10
mL), brine (10 mL), dried (MgSO4) and evaporated under
vacuum. The crude product was recrystallized from CH2Cl2/
hexane to give substituted product.
2-Azido-9,9a-dihydro-1H-quinolizine-4,6-dione (13)
Orange solid; IR (ATR) 3080, 2963, 2105, 1710,
1640, 1398, 1258 cm-1; 1H NMR (CDCl3) d 6.72-6.66 (1H,
m), 6.10 (1H, dd, J = 9.9, 2.4 Hz), 5.77 (1H, d, J = 2.4 Hz),
4.24-4.15 (1H, m), 2.67-2.42 (3H, m), 2.37 (1H, dd, J =
17.4, 4.5 Hz); 13C NMR (CDCl3) d 163.7, 163.2, 152.2,
139.5, 127.2, 109.2, 52.9, 33.2, 31.0; Exact mass calcd for
C9H8N4NaO2 m/z 227.0545 (M++Na), ESI-HRMS m/z
227.0539 (M++Na).
6-Allyl-4-(4-butyl-1H-1,2,3-triazol-1-yl)-1-tosyl-5,6-di-
2-Azido-7-methyl-9,9a-dihydro-1H-quinolizine-4,6-di-
one (14)
hydropyridin-2(1H)-one (18b)
White solid; mp 135.8-136.2 oC (recryst. CH2Cl2); IR
(ATR) 3129, 2942, 2928, 2871, 1677, 1596, 1341, 1170
Orange solid; IR (ATR) 3001, 2107, 1707, 1637,
1235, 1091 cm-1; 1H NMR (CDCl3) d 6.45-6.42 (1H, m),
5.76 (1H, d, J = 2.1 Hz), 4.18-4.11 (1H, m), 2.57 (1H, ddd,
1
cm-1; H NMR (CDCl3) d 7.99 (2H, d, J = 8.4 Hz), 7.62
(1H, s), 7.33 (2H, d, J = 8.4 Hz), 6.07 (1H, d, J = 2.6 Hz),
J. Chin. Chem. Soc. 2012, 59, 365-372
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Article
Chou et al.
5.87-5.73 (1H, m), 5.17-5.00 (3H, m), 3.73 (1H, dd, J =
18.2, 1.2 Hz), 3.20 (1H, ddd, J = 18.2, 6.6, 2.6 Hz), 2.75
(2H, t, J = 7.5 Hz), 2.66-2.47 (2H, m), 2.44 (3H, s), 1.70-
1.63 (3H, m), 1.39 (2H, sextet, J = 7.5 Hz), 0.94 (3H, t, J =
7.2 Hz); 13C NMR (CDCl3) d 162.1, 150.4, 145.9, 145.1,
136.3, 132.6, 129.5, 129.1, 120.2, 118.0, 108.2, 53.7, 38.4,
31.2, 28.3, 25.2, 22.3, 21.7, 13.8; Exact mass calcd for
C21H27N4O3S m/z 415.1804 (M++H), ESI-HRMS m/z
415.1813 (M++H).
FAB-HRMS m/z 281.1393.
6-Allyl-4-(4-butyl-1H-1,2,3-triazol-1-yl)-5,6-dihydro-2-
pyridone (19b)
o
White solid; mp 100.3-101.4 C (recryst. CH2Cl2/
hexane); IR (ATR) 3194, 3151, 3071, 2956, 2924, 2855,
1668, 1629, 1441, 1348, 1235, 1041, 861 cm-1; 1H NMR
(CDCl3) d 7.70 (1H, s), 6.14 (2H, br s), 5.87-5.73 (1H, m),
5.27-5.21 (2H, m), 3.91-3.81 (1H, m), 3.46 (1H, J = dd,
17.5, 5.1 Hz), 2.90 (1H, ddd, J = 17.5, 11.1, 1.5 Hz), 2.77
(2H, t, J = 7.5 Hz), 2.57-2.34 (2H, m), 1.69 (2H, quintet, J =
7.5 Hz), 1.41 (2H, sextet, J = 7.5 Hz), 0.96 (3H, t, J = 7.5
Hz); 13C NMR (CDCl3) d 166.3, 149.9, 145.5, 132.5, 120.1,
117.9, 108.5, 49.5, 39.6, 31.2, 30.2, 25.2, 22.3, 13.8; FAB-
MS (relative intensity) m/z 261 (M++H, 100), 151 (23), 150
(100), 127 (29), 126 (57), 124 (83), 84 (28), 67 (30), 62
(29); Exact mass calcd for C14H21N4O m/z 261.1715
(M++H), FAB-HRMS m/z 261.1717.
6-Allyl-4-(4-methoxycarbonyl-1H-1,2,3-triazol-1-yl)-1-
tosyl-5,6-dihydropyridin-2(1H)-one (18c)
White solid; mp 196.6-197.8 oC (recryst. CH2Cl2); IR
(ATR) 3133, 2955, 2923, 2853, 1719, 1677, 1456, 1260,
1
1167, 1032 cm-1; H NMR (CDCl3) d 8.44 (1H, s), 7.99
(2H, d, J = 8.4 Hz), 7.34 (2H, d, J = 8.4 Hz), 6.29 (1H, d J =
2.7 Hz), 5.86-5.72 (1H, m), 5.18-5.03 (3H, m), 3.99 (3H,
s), 3.62 (1H, dd, J = 18.5, 1.2 Hz), 3.26 (1H, ddd, J = 18.5,
6.9, 2.7 Hz), 2.66-2.44 (2H, m), 2.40 (3H, s); 13C NMR
(CDCl3) d 161.3, 160.3, 145.4, 144.9, 141.3, 136.0, 132.4,
129.5, 129.2, 125.0, 120.4, 111.0, 53.5, 52.7, 38.5, 28.4,
21.8; Exact mass calcd for C19H21N4O5S m/z 417.1233
(M++H), ESI-HRMS m/z 417.1245 (M++H).
6-Allyl-4-(4-methoxycarbonyl-1H-1,2,3-triazol-1-yl)-
5,6-dihydro-2-pyridone (19c)
White solid; mp 176.1 oC (decomp) (recryst. CH2Cl2/
hexane); IR (ATR) 3287, 3147, 2931, 1706, 1627, 1551,
1434, 1343, 1251, 1197, 1033 cm-1; H NMR (CDCl3) d
1
8.51 (1H, s), 6.31 (1H, t, J = 1.8 Hz), 5.86-5.72 (2H, m),
5.34-5.20 (2H, m), 4.00 (3H, s), 3.96-3.86 (1H, m), 3.42
(1H, dd, J = 17.5, 5.1 Hz), 2.92 (1H, ddd, J = 17.5, 11.4, 2.4
Hz), 2.59-2.51 (1H, m), 2.43-2.33 (1H, m); 13C NMR
(CDCl3) d 170.0, 168.7, 149.2, 139.9, 132.8, 119.7, 95.7,
93.3, 51.2, 49.2, 39.6, 33.0; FAB-MS (relative intensity)
m/z 263 (M++H, 100), 150 (63), 127 (23), 126 (44), 124
(55), 62 (21), 60 (23), 53 (23); Exact mass calcd for
C12H15N4O3 m/z 263.1144 (M++H), FAB-HRMS m/z
263.1139.
General procedure for removing the tosyl group of
compounds 18 with Bu3SnH/AIBN
To a refluxing solution of the N-tosyl compound 18
(0.96 mmol) in degassed toluene (10 mL) was added in one
portion a solution of Bu3SnH (1.15 mmol) and AIBN (0.57
mmol) in tolune (2 mL). The reaction mixture was refluxed
for another 2 h. The solvent was then evaporated under
vacuum, and the crude product was purified by flash chro-
matography using ethyl acetate/hexane (1:4-1:1) as eluent
to give the secondary amides 19.
General procedure for the N-allylation of amides 19
To a solution of compound 19a (33 mg, 0.12 mmol)
and HMPA (82.8 mL, 0.78 mmol) in THF (3 mL) at -78 oC
under nitrogen was added dropwise a solution of BuLi (1.6
M in hexane, 95.7 mL, 0.15 mmol). After stirring at -78 oC
for 30 min, allyl bromide (40.8 mL, 0.47 mmol) was added
in one portion, and the reaction mixture was slowly warmed
to room temperature and stirred for another 3 h before it
was poured into saturated ammonium chloride solution (15
mL). The solvent was removed by rotary evaporation, and
the residue was extracted with ethyl acetate (15 mL ´ 3),
dried (MgSO4), and evaporated under vacuum. The crude
product was purified by flash chromatography using ethyl
acetate/hexane (1:8-1:1) as eluent to give purified products
20.
6-Allyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,6-dihydro-
2-pyridone (19a)
o
White solid; mp 160.1-161.5 C (recryst. CH2Cl2/
hexane); IR (ATR) 3204, 3193, 3077, 3067, 1669, 1628,
1
1459, 1439, 1347, 1222, 1018 cm-1; H NMR (CDCl3) d
8.10 (1H, s), 7.89-7.87 (2H, m), 7.50-7.39 (3H, m), 6.25
(1H, t, J = 1.8 Hz), 5.87 (1H, br s), 5.79-5.74 (1H, m),
5.29-5.23 (2H, m), 3.95-3.84 (1H, m), 3.51 (1H, dd, J =
17.5, 5.2 Hz), 2.95 (1H, ddd, J = 17.5, 11.4, 1.8 Hz), 2.60-
2.51 (1H, m), 2.44-2.34 (1H, m); 13C NMR (CDCl3) d
166.1, 149.0, 145.3, 132.4, 129.4, 129.1 (´2), 126.1, 120.2,
116.6, 109.2, 49.5, 39.6, 30.3; FAB-MS (relative intensity)
m/z 281 (M++H, 100), 253 (45), 179 (45), 177 (45), 150
(100), 126 (58), 124 (84), 68 (33), 67 (33), 62 (44); Exact
mass calcd for C16H17N4O m/z 281.1402 (M++H),
370
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© 2012 The Chemical Society Located in Taipei & Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
J. Chin. Chem. Soc. 2012, 59, 365-372

JOURNAL OF THE CHINESE
CHEMICAL SOCIETY
Triazolyl-Substituted Quinolizidine Imides
1,6-Diallyl-4-(4-phenyl-1H-1,2,3-triazol-1-yl)-5,6-di-
11.1, 4.2, 6.9), 3.71 (1H, br d, J = 18.7 Hz), 3.56 (1H, ddd, J
= 18.0, 7.2, 1.2 Hz), 3.22 (1H, ddd, J = 18.0, 6.3, 0.6 Hz),
2.55-2.44 (1H, m), 2.32-2.21 (1H, m); 13C NMR (CDCl3) d
163.9, 149.0, 142.5, 129.5, 129.12, 129.07, 126.2, 124.9,
124.2, 116.3, 109.3, 50.9, 42.9, 31.7, 29.6; FAB-MS (rela-
tive intensity) m/z 293 (M++H, 57), 265 (40), 152 (24), 150
(100), 127 (27), 125 (54), 124 (81), 84 (26), 67 (33), 62
(32); Exact mass calcd for C17H17N4O m/z 293.1402
(M++H), FAB-HRMS m/z 293.1395.
hydro-2-pyridone (20a)
o
White solid; mp 101.8-103.1 C (recryst. CH2Cl2/
hexane); IR (ATR) 3102, 2925, 1666, 1621, 1458, 1438,
1225, 1019 cm-1; 1H NMR (CDCl3) d 8.16 (1H, s), 7.90-
7.86 (2H, m), 7.50-7.37 (3H, m), 6.30 (1H, d, J = 2.4 Hz),
5.93-5.69 (2H, m), 5.30-5.08 (4H, m), 4.76 (1H, ddd, J =
15.6, 3.3, 1.8 Hz), 3.80-3.73 (1H, m), 3.69-3.48 (2H, m),
3.16 (1H, ddd, J = 18.0, 6.9, 2.7 Hz), 2.49-2.39 (2H, m);
13C NMR (CDCl3) d 162.8, 149.0, 142.5, 133.4, 133.2,
129.5, 129.1, 129.0, 126.1, 119.7, 117.8, 116.5, 109.8,
53.6, 47.4, 36.5, 27.8; FAB-MS (relative intensity) m/z 321
(M++H, 7), 59 (72), 53 (70), 52 (100); Exact mass calcd for
C19H21N4O m/z 321.1725 (M++H), FAB-HRMS m/z
321.1710.
2-(4-Butyl-1H-1,2,3-triazol-1-yl)-9,9a-dihydro-1H-
4(6H)-quinolizinone (21b)
White solid; mp 139.8 oC (decomp) (recryst. CH2Cl2/
hexane); IR (ATR) 3140, 2956, 1678, 1664, 1622, 1563,
1423, 1332, 1209, 1039 cm-1; 1H NMR (CDCl3) d 7.70 (1H,
s), 6.14 (1H, t, J = 1.2 Hz), 5.86-5.75 (2H, m), 4.67 (1H, br
d, J = 18.4 Hz), 3.99 (1H, ddt, J = 11.1, 4.5, 6.6 Hz), 3.69
(1H, br d, J = 18.4 Hz), 3.50 (1H, ddd, J = 18.0, 7.2, 1.2
Hz), 3.17 (1H, dd, J = 18.0, 6.0 Hz), 2.77 (2H, t, J = 7.6
Hz), 2.52-2.41 (1H, m), 2.26-2.18 (1H, m), 1.74-1.64 (2H,
m), 1.41 (2H, sextet, J = 7.2 Hz), 0.95 (3H, t, J = 7.2 Hz);
13C NMR (CDCl3) d 164.1, 149.9, 142.6, 124.9, 124.2,
117.7, 108.6, 50.8, 42.8, 31.6, 31.3, 29.5, 25.3, 22.3, 13.8;
FAB-MS (relative intensity) m/z 273 (M++H, 100), 245
(55), 150 (28), 124 (27); Exact mass calcd for C15H21N4O
m/z 273.1715 (M++H), FAB-HRMS m/z 273.1704.
1,6-Diallyl-4-(4-butyl-1H-1,2,3-triazol-1-yl)-5,6-di-
hydro-2-pyridone (20b)
White solid; mp 109-110.7 oC (recryst. CH2Cl2/hex-
ane); IR (ATR) 3140, 3100, 2957, 2927, 2857, 1664, 1619,
1444, 1416, 1208, 1001 cm-1; 1H NMR (CDCl3) d 7.65 (1H,
s), 6.16 (1H, d, J = 2.7 Hz), 5.91-5.68 (2H, m), 5.30-5.06
(4H, m), 4.78-4.69 (1H, m), 3.76-3.68 (1H, m), 3.58-3.48
(2H, m), 3.10 (1H, ddd, J = 18.0, 6.9, 2.7 Hz), 2.76 (2H, t, J
= 7.5 Hz), 2.46-2.36 (2H, m), 1.74-1.64 (2H, m), 1.41 (2H,
sextet, J = 7.5 Hz), 0.96 (3H, t, J = 7.5 Hz); 13C NMR
(CDCl3) d 163.0, 149.9, 142.7, 133.4, 133.3, 119.6, 117.8,
117.7, 109.1, 53.6, 47.4, 36.4, 31.3, 27.8, 25.3, 22.3, 13.8;
FAB-MS (relative intensity) m/z 301 (M++H, 22), 69 (40),
67 (36), 64 (48), 60 (52), 59 (39), 58 (38), 54 (79), 53
(100); Exact mass calcd for C17H25N4O m/z 301.2011
(M++H), FAB-HRMS m/z 301.2028.
ACKNOWLEDGEMENTS
Financial support of this work by the National Sci-
ence Council of the Republic of China is gratefully ac-
knowledged (NSC 97-2113-M-030-MY3).
General procedure for the RCM reaction of com-
pounds 20
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J. Chin. Chem. Soc. 2012, 59, 365-372