Silver- and gold-mediated intramolecular cyclization to substituted tetracyclic isoquinolizinium hexafluorostilbates

Article abstract of DOI:10.1021/jo1006174

A convenient route for the synthesis of various charged tetracyclic isoquinolizinium hexafluorostilbates was developed using AgSbF ₆/AuCl(PPh₃) for the intramolecular addition of amine to alkyne. The described process is tolerant of a variety of functional groups and broadens the diversity of substrates with the use of 8-substituted tetracyclic isoquinolizinium salts.

Full text of DOI:10.1021/jo1006174

pubs.acs.org/joc
Silver- and Gold-Mediated Intramolecular Cyclization to Substituted
Tetracyclic Isoquinolizinium Hexafluorostilbates
Fang Liu,†,‡,§ Xiao Ding,†,§ Lei Zhang,† Yu Zhou,† Linxiang Zhao,‡
Hualiang Jiang,† and Hong Liu*,†
†State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of
Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, and ‡School of Pharmaceutical Engineering,
Shenyang Pharmaceutical University, Shenyang, Liaoning 110016, China
hliu@mail.shcnc.ac.cn
Received March 31, 2010
A convenient route for the synthesis of various charged tetracyclic isoquinolizinium hexafluoros-
tilbates was developed using AgSbF6/AuCl(PPh3) for the intramolecular addition of amine to alkyne.
The described process is tolerant of a variety of functional groups and broadens the diversity of
substrates with the use of 8-substituted tetracyclic isoquinolizinium salts.
Introduction
and functionalization of these alkaloids have invoked con-
siderable interest during recent years, and many potential
routes for the synthesis of such compounds have been
developed.5 However, the classical methods are limited in the
diversity of the configuration of the tetracyclic compounds,
and it is difficult to construct distinct substituted heterocycles.6
The construction of different configurations of heterocyclic
cations, which are the analogues of protoberberine alkaloids
that possibly retain their potential bioactivities, especially the
substitution on the isoquinolizinium-type cations, remains a
challenge for chemists. Therefore, the development of im-
proved methodologies to synthesize new alkaloids with differ-
ent backbone structures still remains highly desirable.
In recent years, transition-metal homogeneous catalysis
has been considered as one of the most promising routes to a
wide range of chemical processes,7 especially, homogeneous
silver and gold catalysis have emerged as powerful tools to
synthesize many N-heterocycles.8 Unlike the catalysts used
in classical methods, silver and gold catalysts used in our
Dihydroisoquinolino[1,2-a]isoquinolizinium-type cations1
are versatile heterocyclic compounds found in many natural2
and synthetic products and are well-known for their potent
biological activities. Heterocyclic compounds, especially pro-
toberberine alkaloids (palmatine,3a jateorrhizine,3b epiber-
berine,3c coptisine,3d groenlandicine,3e and berberine3f) have
attracted considerable attention from chemists due to their
variety of activities, including a strong inhibitory potency
against Alzheimer’s disease4 (Figure 1). Therefore, the synthesis
§ These authors contributed equally to this work.
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Gonzalez, J. F. Bioorg. Med. Chem. 2008, 16, 9056.
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M.; Enders, D. J. Org. Chem. 2005, 70, 9486.
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5810 J. Org. Chem. 2010, 75, 5810–5820
Published on Web 08/04/2010
DOI: 10.1021/jo1006174
r
2010 American Chemical Society

Liu et al.
JOCArticle
FIGURE 1. Representative dihydroisoquinolizinium-type cations in medicinal chemistry and natural products.
TABLE 1. Optimization of the Reaction Conditionsa
method are very effective and popular in reactions involving
intermolecular and intramolecular nucleophilic substitu-
tions on alkynes, owing to their exceptional ability to acti-
vate π-systems.9 Our long-term interests in novel synthesis of
biologically active heterocyclic compounds using transition-
metal catalysts10 led us to investigate the cyclization of tetra-
cyclic isoquinolizinium. Herein, we report in detail the con-
struction of novel cationic alkaloids in the presence of silver
and gold salts.
Conventional routes to alkaloids are long and com-
plicated;11 moreover, the substrates are limited in the diver-
sity of the configuration of tetracycles and the low substitu-
tion possibility on the C-ring. Our method can be used to
construct diverse and new 8-substituted dihydroisoquino-
lino[1,2-a]isoquinolizinium cationic alkaloids under mild
conditions using silver and gold salts as catalysts. This new
configuration of tetracyclic compounds is similar to the
protoberberine alkaloids and is expected to exhibit similar
biological activities.12 The interesting 8-substituted isoqui-
nolizinium will widen the category and quantity of alkaloid
derivatives that can be formed. To the best of our knowledge,
the synthesis of such substituted heterocyclic compounds has
not yet been reported. The process has several distinguished
features: (1) this is the first report on the synthesis of new di-
hydroisoquinolino[1,2-a]isoquinolizinium cations, and these
entry
catalyst
solvent time (h) yieldb (%)
1
2
3
4
5
6
7
8
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
DMF
CH2Cl2
THF
24
24
24
24
24
24
24
24
24
48
24
24
24
0
0
0
0
0
0
0
0
20%CuI
20%PdCl2
20%RuCl3.xH2O
20%K2PtCl4
20% AgOTf
20% AgOAc
20% Ag2CO3
20% AgSbF6
20% AgSbF6
20% AgSbF6
20% AgSbF6
20% AgSbF6
20% AgSbF6
50% AgSbF6
50% AgSbF6
100% AgSbF6
100% AgSbF6
100% AgSbF6/10% AuCl
100% AgSbF6/10%AuCl3
100% AgSbF6/10% AuCl(PPh3) PhMe
100% AgSbF6/20% AuCl(PPh3) PhMe
100% AgSbF6/10% AuCl(PPh3) PhMe
9
20
21
0
<10
trace
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
CH3CN 24
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
24
48
24
48
12
12
12
12
48
48
48
48
38
40
65
67
64
66
78
77
75
15
0
(8) (a) Weibel, J. M.; Blanc, A.; Pale, P. Chem. Rev. 2008, 108, 3149.
(b) Alvarez-Corral, M.; Munoz-Dorado, M.; Rodirguez-Garcia, I. Chem.
Rev. 2008, 108, 3174. (c) Widenhoefer, R. A.; Han, X. Q. Eur. J. Org. Chem.
2006, 71, 4555. (d) Belmont, P.; Parker, E. Eur. J. Org. Chem. 2009, 74, 6075.
24 c 100% AgSbF6/10% AuCl(PPh3) PhMe
ꢀ
(e) Weber, D.; Gagne, M. R. Org. Lett. 2009, 11, 4962.
25
26
100% TfOH/10% AuCl(PPh3)
100% AuCl(PPh3)
PhMe
PhMe
(9) (a) Sun, J.; Conley, M. P.; Zhang, L.; Kozmin, S. A. J. Am. Chem. Soc.
2006, 128, 9705. (b) Ferrer, C.; Echavarren, A. M. Angew. Chem. 2006, 45,
1105. (c) Hildebrandt, D.; Dyker, G. J. Org. Chem. 2006, 71, 6728.
(10) (a) Zhou, Y.; Zhai, Y.; Ji, X.; Liu, G.; Feng, E.; Ye, D.; Zhao, L.;
Jiang, H.; Liu, H. Adv. Synth. Catal. 2010, 352, 373. (b) Ye, D.; Zhang, X.;
Zhou, Y.; Zhang, D.; Zhang, L.; Wang, H.; Jiang, H.; Liu, H. Adv. Synth.
Catal. 2009, 351, 2770. (c) Zhou, Y.; Feng, E.; Liu, G.; Ye, D.; Li, J.; Jiang,
H.; Liu, H. J. Org. Chem. 2009, 74, 7344. (d) Liu, G.; Zhou, Y.; Ye, D.;
Zhang, D.; Ding, X.; Jiang, H.; Liu, H. Adv. Synth. Catal. 2009, 351, 2605.
(e) Ye, D.; Wang, J.; Zhang, X.; Zhou, Y.; Ding, X.; Feng, E.; Sun, H.; Liu,
G.; Jiang, H.; Liu, H. Green Chem. 2009, 11, 1201. (f) Huang, H.; Jiang, H.;
Chen, K.; Liu, H. J. Org. Chem. 2009, 74, 5476. (g) Feng, E.; Huang, H.;
Zhou, Y.; Ye, D.; Jiang, H.; Liu, H. J. Org. Chem. 2009, 74, 2846. (h) Li, Z.;
Sun, H.; Jiang, H.; Liu, H. Org. Lett. 2008, 10, 3263.
0
27d 100% AgSbF6/10% AuCl(PPh3) PhMe
0.5
12
55
76
28e 100% AgSbF6/10% AuCl(PPh3) PhMe
aThe reaction was carried out in the presence of catalysts in anhy-
drous solvent at 110 °C under argon protection unless otherwise noted.
bYields of isolated products based on 1. cThe reaction was carried out at
80 °C. dThe reaction was carried out under microwave irradiation (The
temperature was measured by fiber optics inside the reaction vial). eThe
reaction was carried out without argon protection.
diverse analogues of cationic alkaloids can be obtained in
moderate to good yields; (2) this study provides an efficient
method for the metal-mediated synthesis of new tetrahetero-
cycles via the intramolecular addition of amines to alkynes,
unlike that in the classical methods.
(11) (a) Toullec, P. Y.; Genin, E.; Leseurre, L.; Genet, J. P.; Michelet, V.
Angew. Chem., Int. Ed. 2006, 45, 7427. (b) Asao, N.; Aikawa, H.; Tago, S.;
Umetsu, K. Org. Lett. 2007, 9, 4299.
(12) Barbara, H.; Michael, D.; Patrick, M.; Astrid, M. S.; Sherif, A. F.
J. Med. Chem. 2006, 49, 760.
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TABLE 2. Synthesis of Tetracyclic Isoquinolizinium Hexafluorostilbates with R1 Substitutentsa
aThe reaction was carried out in the presence of AgSbF6 (100 mol %) and AuCl(PPh3) (10 mol %) in anhydrous toluene at 110 °C unless otherwise
noted. bYields of isolated products based on 1. cThe reactant was recovered.
Results and Discussion
lysts (different equivalents) and solvents. As shown in Table 1,
under catalyst-free conditions the reaction did not occur,
and only the starting material 1a was recovered (entry 1,
Table 1). Similarly, the reactions did not occur in the pre-
The optimal conditions were determined using 1a13 as a
model substrate and by varying the concentrations of cata-
sence of CuI, PdCl2, RuCl3 xH2O, K2PtCl4, AgOTf, AgOAc,
3
and Ag2CO3 (entries 2-8, Table 1). Product 2a was obtained
(13) For the synthesis of 1a, see the Experimental Section.
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JOCArticle
TABLE 3. Synthesis of Tetracyclic Isoquinolizinium Hexafluorostilbates with R1 and/or R2 Substitutentsa
aThe reaction was carried out in the presence of AgSbF6 (100 mol %) and AuCl(PPh3) (10 mol %) in anhydrous toluene at 110 °C unless otherwise
noted. bYields of isolated products based on 1. cThe reactant was recovered.
J. Org. Chem. Vol. 75, No. 17, 2010 5813

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SCHEME 1. Plausible Mechanism for the Cyclization
in 20% yield when 0.2 equiv of AgSbF6 dissolved in anhydrous
toluene was used at 110 °C for 24 h (entry 9, Table 1).
Increasing the reaction time to 48 h did not improve the
product yield (entry 10, Table 1). Polar solvents were found
to have a detrimental effect on the reaction, and anhydrous
toluene was confirmed to be the optimum solvent (entries
11-14, Table 1). When a stoichiometric amount of AgSbF6
was used, the yield of product 2a obviously increased to 65%
(entry 17, Table 1). However, prolonging the reaction time did
not substantially improve the yield (entries 16 and 18, Table 1).
To accelerate the reaction, we used various cocatalysts (entries
19-24, Table 1). The addition of 10% AuCl(PPh3) could
noticeably promote the intramolecular cyclization and de-
crease the reaction time, affording 2a in 78% yield (entry 21,
Table 1). Similar yields were obtained even when the amount
of cocatalysts was increased or the reaction time was prolonged
(entries 22 and 23, Table 1). In addition, the reaction tempera-
ture was found to play an important role in the process. For
example, the yield of compound 2a was only 10% when the
temperature was reduced to 80 °C (entry 24, Table 1). We have
done control experiments with 100% TfOH and 10% AuCl-
(PPh3); it did not work (entry 25, Table 1). We have also done
control experiments with 100% AuCl(PPh3) only, and it did
not work (entry 26, Table 1). We also performed the reaction
under microwave irradiation at 110 °C for 30 min and could
obtain only 55% the yield (entry 27, Table1), indicating that
the classical heating method is more effective. Last, we per-
formed the reaction without argon protection, and a similar
yield (76%) was obtained (entries 21 and 28, Table 1).
Under the optimized reaction conditions (1.0 equiv of
AgSbF6, 0.1 equiv of AuCl(PPh3), PhMe, 110 °C, 12 h, as
shown in entry 28, Table 1), we then examined the generality
of the process. The results are summarized in Tables 2 and 3.
A variety of alkynes, including aliphatic, aromatic, and
heterocyclic substitutents, were investigated (Table 2). The
aliphatic alkynes generated the desired products in moderate
yields (entries 3-6, Table 2). Steric hindrance strongly
affected the reaction, and only a trace amount of 2b was
obtained (entry 2, Table 2). However, the alkynes with aro-
matic substituents produced higher yields (entries 7-13,
Table 2). Better results were observed with electron-donating
substitutents on the aromatic ring, presumably due to the
electronic effect (entries 7, 8, and 11-13, Table 2). The ortho,
meta, or para substitution on the aromatic ring of R1 did not
significantly affect the yields (entries 11-13, Table 2). Sub-
strate 1n with a heterocyclic substituted alkyne and 1o with a
terminal alkyne did not generate the desired products under
the optimized conditions (entries 14 and 15, Table 2).
To further broaden the scope of this method, we also
examined the influence of substitution on the A ring. As
shown in Table 3, corresponding product yields increased
greatly when the A ring was substituted by electron-donating
groups. Similarly, substrates with aliphatic substituted al-
kyne moieties generated moderate to good yields (entries
1-5, Table 3). Steric hindrance strongly affected the reac-
tion, and only a trace amount of 4d was observed (entry 4,
Table 3). We also examined the steric and electron effects of
various substitutents on the aromatic alkyne. We found that
the steric and electron effects did not significantly influence
the reaction, and moderate product yields were obtained
(entries 6-12, Table 3). The indole-substituted substrates
could generate moderate yields of corresponding products
(entries 13-18, Table 3). When the A ring was fused with a
benzene or thiofuran ring or methoxyl phenyl moieties, 4s,
4t, and 4u could be generated in 72%, 74%, and 70% yields,
respectively (entries 19-21, Table 3).
1
The structure of 2a is confirmed by H nuclear magnetic
resonance (NMR) spectroscopy, 13C NMR spectroscopy,
mass spectroscopy, and X-ray crystallography (see the Sup-
porting Information).14
(14) CCDC 762577 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
5814 J. Org. Chem. Vol. 75, No. 17, 2010

Liu et al.
On the basis of the above-mentioned findings, a plausible
JOCArticle
mixture was then heated under an argon atmosphere at 80 °C.
The reaction was monitored by TLC to establish completion.
When the reaction was complete, the mixture was allowed to
cool to room temperature, and the solvent was removed under
reduced pressure. The residue was purified by column chroma-
tography on silica gel with petroleum ether (PE)/EtOAc (8/1,
v/v) as eluent to afford the corresponding compounds. Then
compound from the above procedure (1.0 mmol) was diluted in
10 mL of a TFA/CH2Cl2 1:1 mixture. After the mixture was
stirred at room temperature for 1 h, the solvent was evaporated
to afford 1a: 1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 7.2 Hz,
1H), 7.52-7.49 (m, 2H), 7.39-7.31 (m, 5H), 7.22 (d, J = 7.5 Hz,
1H), 7.17-7.13 (m, 3H), 7.77 (d, J = 7.8 Hz, 1H), 6.16 (s, 1H),
3.59 (br s, 1H), 3.20 (br s, 1H), 2.80 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 138.2 132.8 132.2 131.8 130.0 129.2 128.9 128.8 128.3
128.0 127.1 124.1 122.2 117.9 95.7 85.4 57.2 39.9 25.6; MS (EI,
m/z) 309 [M]þ; HRMS (EI) calcd for C23H19N [M]þ 309.1517,
found 309.1520.
1-(2-(Pent-1-ynyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1c):
1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 8.4 Hz, 1H),
7.19-7.18 (m, 3H), 7.14-7.10 (m, 3H), 6.93 (t, J = 7.8 Hz,
1H), 6.19 (s, 1H), 4.28 (br s, 1H), 3.36 (t, J = 7.5 Hz, 1H),
2.99-2.96 (m, 1H), 2.89 (s, 1H), 2.43 (t, J = 7.8 Hz, 2H),
1.81-1.73 (m, 2H), 0.77 (t, J = 7.2 Hz, 3H); 13C NMR (75 MHz,
CDCl3) δ 147.3 139.6 135.2 135.0 128.7 128.6 128.6 127.9 126.7
126.2 100.7 80.3 61.8 40.0 36.5 29.4 26.8 23.4; MS (EI, m/z) 275
[M]þ; HRMS (EI) calcd for C20H21N [M]þ 275.1674, found
275.1660.
mechanism was proposed in Scheme 1. As has been postulated
for other Au-catalyzed nucleophilic additions, the catalyst
used in our method is a cationic gold complex typically
precipitated from AgSbF6 and AuCl(PPh3).15 Initial activa-
tion of the gold catalyst to the alkyne function allows the
formation of a transient intermediate (6). Intramolecular
nucleophilic addition of the amine on the activated alkyne
affords the intermediate 7,16 which on subsequent oxidative
aromatization (8) and complexation with hexafluoro anti-
monate anion generates the tetracyclic isoquinoline hexafluoro-
stilbates 9 and metallic gold. Product 9 is stable due to the
conjugated system.
Conclusion
In summary, we have developed a mild strategy to synthe-
size a class of tetracyclic isoquinolizinium salts in moderate
to good yields via silver- and gold-cocatalyzed intramo-
lecular cyclization. Because of the biological activities of iso-
quinoline alkaloids, it is speculated that these new biologi-
cally intriguing structures will find broad applications in
medicinal chemistry programs. Further studies to elucidate
the precise mechanism underlying these reactions and to
extend the scope of their synthetic utilities are in progress in
our laboratory.
1-(2-(4-Methylpent-1-ynyl)phenyl)-1,2,3,4-tetrahydroisoqui-
noline (1d): 1H NMR (300 MHz, CDCl3) δ 7.43 (d, J = 7.2 Hz,
2H), 7.21 (t, J = 7.5 Hz, 2H), 7.19-7.12 (m, 2H), 6.91 (t, J = 7.5
Hz, 2H), 5.70 (s, 1H), 3.82 (br s, 1H), 3.37 (br s, 1H), 2.77 (br,
2H), 2.35 (d, J = 4.8 Hz, 2H), 1.93-1.88 (m, 1H), 1.03 (s, 3H),
1.02 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 147.4 144.0 139.7
135.3 128.8 128.7 128.4 128.0 126.8 126.3 100.8 80.4 61.9 40.1
31.3 29.5 28.6 22.5; MS (EI, m/z) 289 [M]þ; HRMS (EI) calcd for
C21H23N [M]þ 289.1830, found 289.1851.
Experimental Section
Typical Procedure for the Synthesis of 1-(2-(Phenylethynyl)-
phenyl)-1,2,3,4-tetrahydroisoquinoline (1a). To a solution of
EDCI (1.2 mmol) and 2-iodobenzoic acid (1 mmol) in CH2Cl2
(20 mL) was added triethylamine (1.2 mmol), followed by
addition of amines (1 mmol) 1 h later. The resulting mixture
was stirred overnight under room temperature. When the start-
ing materials were completely consumed as monitored with
TLC, the reaction mixture was diluted with CH2Cl2, washed
successively with water, aqueous HCl, saturated NaHCO3, and
brine, and dried by anhydrous Na2SO4. Evaporation of the sol-
vent followed by chromatography on a short silica gel column
with petroleum ether (PE)/EtOAc (4/1, v/v) as eluent afforded
crude product 2-iodobenzamides. To a solution of the corre-
sponding 2-iodophenylacetamides (1.0 mmol) in acetonitrile
was added phosphoryl trichloride (5.0 mmol), and the resulting
mixture was stirred for 2 h at 80 °C and monitored by TLC to
establish completion. When the reaction was complete, the
solvent was removed under reduced pressure. The residue was
washed with NaHCO3, the solvent was removed under reduced
pressure, the residue was dissolved in CH3OH, and NaBH4 (5.0
mmol) was added for 2 h at room temperature. The solvent was
removed under reduced pressure, and the residue was washed
with NH4Cl; when the solvent was removed under reduced
pressure, the residue was dissolved in 1,4-dioxnne/2 N NaOH
aq, (Boc)2O (5.0 mmol) was added for 1 h at 80 °C, and the
reaction was monitored by TLC to establish completion. When
the reaction was complete, the solvent was removed under
reduced pressure, and the residue was purified by column
chromatography. To a solution of the residue (1.0 mmol) and
the terminal alkyne (1.2 mmol) in Et3N (5 mL) were added
Pd(PPh3)2Cl2 (0.02 mmol) and CuI (0.01 mmol). The resulting
1-(2-(5-Chloropent-1-ynyl)phenyl)-1,2,3,4-tetrahydroisoquino-
1
line (1e): H NMR (300 MHz, CDCl3) δ 7.46 (d, J = 7.2 Hz,
1H), 7.36 (d, J = 7.2 Hz, 2H), 7.20 (t, J = 7.5 Hz, 2H), 6.99 (t,
J = 7.2 Hz, 2H), 6.91 (t, J = 7.2 Hz, 1H), 5.81 (s, 1H), 4.20 (br,
2H), 3.69 (t, J = 6.3 Hz, 2H), 2.99-2.95 (m, 2H), 2.66 (t, J = 6.9
Hz, 2H), 2.10-2.02 (m, 2H); 13C NMR (75 MHz, CDCl3) δ
146.0 139.6 136.0 135.0 134.5 132.3 128.7 128.5 127.8 126.7
126.6 100.7 79.9 61.9 43.6 36.5 31.3 29.4 17.1; MS (EI, m/z) 309
[M]þ; HRMS (EI) calcd for C20H20ClN [M]þ 309.1284, found
309.1296.
1-(2-(3-Cyclohexylprop-1-ynyl)phenyl)-1,2,3,4-tetrahydroiso-
quinoline (1f): 1H NMR (300 MHz, CDCl3) δ 7.63 (d, J = 7.5
Hz, 1H), 7.43-7.41 (m, 1H), 7.21 (t, J = 7.2 Hz, 2H), 7.15-7.13
(m, 2H), 6.92 (t, J = 8.4 Hz, 2H), 6.10 (s, 1H), 4.12 (br, 2H),
2.93-2.88 (m, 2H), 2.34 (d, J = 6.6 Hz, 2H), 1.23-1.11 (m,
11H); 13C NMR (75 MHz, CDCl3) δ 139.6 136.2 135.3 128.8
128.7 128.4 128.0 126.7 126.4 126.3 100.7 80.4 62.0 40.0 37.4 32.7
29.5 27.4 26.2 26.1; MS (EI, m/z) 329 [M]þ; HRMS (EI) calcd for
C24H27N [M]þ 329.2143, found 329.2147.
1-(2-(p-Tolylethynyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (1g):
1H NMR (300 MHz, CDCl3) δ 7.62 (d, J = 7.5 Hz, 1H),
7.52-7.49 (m, 2H), 7.52-7.39 (m, 5H), 7.22 (s, 1H), 7.14 (d,
J = 7.8 Hz, 2H), 6.77 (d, J = 7.8 Hz, 1H), 6.16 (s, 1H), 4.21 (br,
1H), 3.37 (br, 1H), 3.01-2.96 (m, 2H), 2.37 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 147.2 139.6 138.4 136.2 135.3 135.0 134.4
132.3 131.5 129.0 128.8 128.7 128.4 128.0 126.7 126.3 120.0 100.7
80.4 61.9 40.0 29.5 21.5; MS (EI, m/z) 323 [M]þ; HRMS (EI)
calcd for C24H21N [M]þ 323.1674, found 323.1675.
(15) (a) Toullec, P. Y.; Genin, E.; Leseurre, L.; Genet, J. P.; Michelet, V.
Angew. Chem., Int. Ed. 2006, 45, 7427. (b) Asao, N.; Aikawa, H.; Tago, S.;
Umetsu, K. Org. Lett. 2007, 9, 4299.
(16) (a) Asao, N; Yudha, S. S.; Nogami, T.; Yamamoto, Y. Angew.
Chem., Int. Ed. 2005, 44, 5526. (b) Asao, N.; Iso, K.; Yudha, S. S. Org. Lett.
2006, 8, 4149. (c) Huo, Z.; Yamamoto, Y. Tetrahedron Lett. 2009, 50, 3651.
1-(2-((4-tert-Butylphenyl)ethynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (1h):1HNMR(300MHz,CDCl3) δ7.92 (d, J=7.2Hz,
1H), 7.56-7.52 (m, 3H), 7.37-7.34 (m, 3H), 7.17-7.09 (m, 4H),
J. Org. Chem. Vol. 75, No. 17, 2010 5815

Liu et al.
JOCArticle
7.01 (d, J = 8.7 Hz, 1H), 6.10 (s, 1H), 3.79 (br, 1H), 3.37 (br, 1H),
2.93-2.89 (m, 1H), 2.79 (br, 1H), 1.36 (s, 9H); 13C NMR (75 MHz,
CDCl3) δ155.0 147.2 140.0 136.2 135.3 135.1 131.3 128.8 128.7 128.4
128.0 126.8 125.3 120.3 100.8 80.4 62.0 40.1 31.1 29.5 28.2; MS (EI,
m/z) 365 [M]þ; HRMS (EI) calcd for C27H27N [M]þ 365.2143,
found 365.2157.
1-(2-((4-Fluorophenyl)ethynyl)phenyl)-1,2,3,4-tetrahydroiso-
quinoline (1i): 1H NMR (300 MHz, CDCl3) δ 7.61-7.58 (m, 3H),
7.42 (d, J = 7.2 Hz, 2H), 7.24-7.16 (m, 5H), 7.05 (t, J = 8.7 Hz,
2H), 6.21 (s, 1H), 4.21 (br, 1H), 3.70 (br, 1H), 3.03-3.00 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 155.1 139.6 136.0 135.0
134.5 133.5 132.3 128.7 128.6 128.0 127.8 126.7 126.4 126.3 122.4
119.4 115.6 115.4 100.7 80.0 61.9 40.1 29.5; MS (EI, m/z) 327
[M]þ; HRMS (EI) calcd for C23H18FN [M]þ 327.1423, found
327.1434.
147.4 140.0 139.1 135.2 129.2 128.7 128.4 127.2 127.0 111.0 110.7
100.3 80.3 61.5 55.9 55.8 46.1 32.1 30.2 27.1 26.1 26.0 22.2 16.0;
MS (EI, m/z) 377 [M]þ; HRMS (EI) calcd for C25H31NO2 [M]þ
377.2335, found 377.2340.
6,7-Dimethoxy-1-(2-(4-methylpent-1-ynyl)phenyl)-1,2,3,4-tet-
rahydroisoquinoline (3c): 1H NMR (300 MHz, CDCl3) δ
7.43-741 (m, 1H), 7.21 (t, J = 7.2 Hz, 1H), 6.91 (t, J = 7.5
Hz, 2H), 6.63 (s, 2H), 5.80 (s, 1H), 4.13 (br s, 1H), 3.83 (s, 3H),
3.71 (s, 3H), 3.38 (br s, 1H), 2.77 (br, 2H), 2.35 (d, J = 5.7 Hz,
2H), 1.93-1.89 (m, 1H), 1.03 (d, J = 1.8 Hz, 3H), 1.02 (d, J =
1.8 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 147.8 147.4 140.0
135.3 128.7 128.4 128.2 127.2 127.0 111.2 111.0 110.7 100.3 80.3
61.6 55.8 55.7 40.9 32.1 28.9 28.5 22.2; MS (EI, m/z) 349 [M]þ;
HRMS (EI) calcd for C23H27NO2 [M]þ 349.2042, found
349.2045.
1-(2-((4-Chlorophenyl)ethynyl)phenyl)-1,2,3,4-tetrahydroiso-
quinoline (1j): 1H NMR (300 MHz, CDCl3) δ 7.57 (d, J = 7.5
Hz, 1H), 7.31 (s, 2H), 7.25-7.23 (m, 4H), 7.18-7.16 (m, 4H),
6.93 (d, J = 8.1 Hz, 1H), 6.00 (s, 1H), 4.31-4.18 (br, 2H),
3.02-2.98 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 155.1 139.6
136.0 135.3 134.5 134.2 132.8 132.4 128.7 128.6 128.5 128.0 127.8
126.8 126.7 126.5 126.3 121.8 100.7 80.0 61.9 36.6 24.6; MS (EI,
m/z) 343 [M]þ; HRMS (EI) calcd for C23H18ClN [M]þ 343.1128,
found 343.1130.
1-(2-((2-Methoxyphenyl)ethynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (1k): 1H NMR (300 MHz, CDCl3) δ 7.56 (d, J = 8.4
Hz, 1H), 7.43-7.41 (m, 1H), 7.21 (t, J = 7.5 Hz, 2H), 7.15-7.13
(m, 3H), 6.92 (t, J = 8.4 Hz, 3H), 6.62 (d, J = 8.1 Hz, 2H), 6.10
(s, 1H), 4.12 (br s, 2H), 3.84 (s, 3H), 2.91-2.88 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 159.5 152.2 140.5 138.9 138.5 136.0
134.0 133.0 131.6 131.0 130.2 128.1 127.7 126.6 125.8 125.0 124.0
115.8 90.0 80.2 62.2 56.2 40.0 27.6; MS (EI, m/z) 339 [M]þ;
HRMS (EI) calcd for C24H21NO [M]þ 339.1623, found
339.1626.
1-(2-((3-Methoxyphenyl)ethynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (1l): 1H NMR (300 MHz, CDCl3) δ 7.88 (d, J = 8.1
Hz, 2H), 7.70 (s, 1H), 7.56-7.50 (m, 1H), 7.23-7.18 (m, 3H),
6.91 (t, J = 7.8 Hz, 3H), 6.75 (d, J = 8.7 Hz, 2H), 6.09 (s, 1H),
4.09 (br s, 2H), 3.80 (s, 3H), 3.10 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 165.6 148.4 138.7 138.5 136.0 134.0 133.0 131.5 131.0
130.2 128.1 127.7 126.6 125.6 125.0 124.0 120.1 110.8 98.2 90.0
60.1 55.5 42.0 27.6; MS (EI, m/z) 339 [M]þ; HRMS (EI) calcd for
C24H21NO [M]þ 339.1623, found 339.1620.
1-(2-((4-Methoxyphenyl)ethynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (1m): 1H NMR (300 MHz, CDCl3) δ 7.58-7.48 (dd,
J = 14.1, 6.9 Hz, 3H), 7.32 (s, 1H), 7.22-7.20 (m, 3H), 7.16-
7.14 (m, 3H), 6.88 (d, J = 8.7 Hz, 2H), 5.94 (s, 1H), 4.17 (br, 2H),
3.82 (s, 3H), 3.00 (br s, 2H); 13C NMR (75 MHz, CDCl3) δ 155.2
139.0 136.2 132.9 132.0 131.4 129.4 129.2 127.3 126.4 122.1 121.8
119.6 119.4 118.2 118.1 111.0 110.6 95.1 80.2 62.0 55.4 41.2 21.2;
MS (EI, m/z) 339 [M]þ; HRMS (EI) calcd for C24H21NO [M]þ
339.1623, found 339.1627.
6,7-Dimethoxy-1-(2-(pent-1-ynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (3a): 1H NMR (300 MHz, CDCl3) δ 7.44-7.41 (m,
1H), 7.15 (br, 2H), 6.92 (t, J = 7.5 Hz, 1H), 6.64 (s, 1H), 6.62 (s,
1H), 5.95 (s, 1H), 4.11 (br, 1H), 3.84 (s, 3H), 3.71 (s, 3H), 3.37
(br, 1H), 2.95-2.87 (m, 2H), 2.66 (t, J = 6.9 Hz, 3H), 2.07 (t,
J = 6.9 Hz, 2H), 0.91-0.84 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 147.8 147.4 132.2 128.7 128.2 128.0 127.3 127.1 126.7
111.2 111.0 110.4 100.0 82.3 63.9 55.9 55.8 43.7 36.6 31.3 28.2
17.1; MS (EI, m/z) 335 [M]þ; HRMS (EI) calcd for C22H25NO2
[M]þ 335.1885, found 335.1890.
6,7-Dimethoxy-1-(2-(oct-1-ynyl)phenyl)-1,2,3,4-tetrahydro-
isoquinoline (3b): 1H NMR (300 MHz, CDCl3) δ 7.37-7.34 (m,
2H), 7.21 (t, J = 7.2 Hz, 1H), 6.92 (t, J = 7.5 Hz, 1H), 6.64 (s,
2H), 6.08(s, 1H), 4.15 (br s, 1H), 3.85 (s, 3H), 3.73 (s, 3H), 3.36
(br s, 1H), 2.92-2.89 (m, 1H), 2.77 (br s, 1H), 1.50-1.26 (m,
11H), 0.90-0.84 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 147.8
1-(2-(3-Cyclohexylprop-1-ynyl)phenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (3e): 1H NMR (300 MHz, CDCl3) δ 7.42
(br s, 1H), 7.21 (t, J = 7.5 Hz,1H), 7.15-7.13 (m, 1H), 6.92 (t,
J = 8.4 Hz, 1H), 6.64 (s, 1H), 6.61 (s, 1H), 5.70 (s, 1H), 4.13 (br s,
1H), 3.84 (d, J = 5.4 Hz, 3H), 3.71(d, J = 5.7 Hz, 3H), 3.37 (br s,
1H), 2.93-2.88 (m, 2H), 2.35 (d, J = 6.6 Hz, 1H), 2.16 (s, 1H),
1.84 (br, 1H), 1.25-0.99 (m, 10H); 13C NMR (75 MHz, CDCl3)
δ 147.8 147.4 140.0 128.7 128.2 127.2 127.0 126.4 111.2 111.0
110.7 110.5 100.3 80.3 61.5 55.8 55.7 50.0 39.4 34.0 29.2 28.9 27.2
26.0; MS (EI, m/z) 389 [M]þ; HRMS (EI) calcd for C26H31NO2
[M]þ 389.2355, found 389.2360.
1-(2-((4-tert-Butylphenyl)ethynyl)phenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (3f): 1H NMR (300 MHz, CDCl3) δ 7.53
(d, J = 7.2 Hz, 1H), 7.43-7.33 (m, 3H), 7.20 (d, J = 7.5 Hz, 2H),
6.93 (t, J = 8.4 Hz, 2H), 6.65 (s, 2H), 5.92 (s, 1H), 4.17 (br s, 1H),
3.86 (s, 3H), 3.74 (s, 3H), 3.36 (br s, 1H), 2.93-2.90 (m, 1H), 2.79
(br, 1H), 1.36 (br s, 9H); 13C NMR (75 MHz, CDCl3) δ
149.0148.3 135.6 133.8 131.3 130.4 130.0 128.3 128.0 136.4
125.0 124.7 124.4 118.9 115.9 114.1 121.0 110.8 100.3 80.3 61.6
56.7 42.0 31.1 30.1 27.2; MS (EI, m/z) 425 [M]þ; HRMS (EI)
calcd for C29H31NO2 [M]þ 425.2355, found 425. 2361.
6,7-Dimethoxy-1-(2-(p-tolylethynyl)phenyl)-1,2,3,4-tetrahy-
droisoquinoline (3g): 1H NMR (300 MHz, CDCl3) δ 7.56 (s, 1H),
7.44 (br, 2H), 7.14 (d, J = 7.8 Hz, 3H), 6.92 (t, J = 7.5 Hz, 2H),
6.95 (s, 1H), 6.62 (s, 1H), 5.97 (s, 1H), 4.13 (br, 1H), 3.86 (s, 3H),
3.84 (s, 3H), 3.37 (br, 1H), 2.92 (s, 2H), 2.36 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 147.7 147.3 144.0 140.0 138.4 131.3 129.0
128.7 128.3 128.0 127.1 127.0 126.6 120.0 116.0 111.1 110.0 110.6
100.2 80.2 61.5 55.8 55.7 41.1 29.1 21.4; MS (EI, m/z) 383 [M]þ;
HRMS (EI) calcd for C26H25NO2 [M]þ 383.1885, found
383.1882.
6,7-Dimethoxy-1-(2-((2-methoxyphenyl)ethynyl)phenyl)-1,2,3,4-
tetrahydroisoquinoline (3h): 1H NMR (300 MHz, CDCl3) δ 7.82
(d, J = 8.1 Hz, 1H), 7.62 (d, J = 8.1 Hz, 1H), 7.39 (br s, 2H), 7.21
(d, J = 7.2 Hz, 2H), 7.07-7.02 (m, 1H), 6.93 (t, J = 7.5 Hz, 1H),
6.65 (s, 2H), 6.11 (s, 1H), 4.13 (br, 1H), 3.86 (s, 3H), 3.84 (s, 3H),
3.74 (s, 3H), 3.39 (br, 1H), 2.92 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 160.0 152.7 152.0 148.3 143.6 138.8 135.7 134.5 133.3
131.4 130.7 130.7 130.3 128.1 124.9 121.8 121.0 118.4 115.4 96.1
84.1 64.2 56.9 56.7 55.8 41.0 27.0; MS (EI, m/z) 399 [M]þ;
HRMS (EI) calcd for C26H25NO3 [M]þ 399.1834, found
399.1837.
6,7-Dimethoxy-1-(2-((3-methoxyphenyl)ethynyl)phenyl)-1,2,3,4-
tetrahydroisoquinoline (3i): 1H NMR (300 MHz, CDCl3) δ
7.71-7.67 (m, 1H), 7.59 (s, 1H), 7.35 (d, J = 7.2 Hz, 1H),
7.20 (t, J = 7.2 Hz, 1H), 7.10-7.06 (m, 2H), 6.90 (t, J = 8.1 Hz,
1H), 6.80 (d, J = 7.2 Hz, 1H), 6.64 (s, 2H), 6.08 (s, 1H), 4.15 (br
s, 2H), 3.85 (s, 3H), 3.72 (s, 3H), 3.56 (s, 3H), 2.77 (s, 2H); 13
C
NMR (75 MHz, CDCl3) δ 160.0 148.1 147.8 143.6 141.1 138.6
135.5 133.9 133.5 130.4 128.1 125.0 124.4 121.9 118.9 117.4 116.0
115.0 96.0 82.1 63.0 56.8 56.7 56.0 40.0 27.2; MS (EI, m/z) 399
[M]þ; HRMS (EI) calcd for C26H25NO3 [M]þ 399.1834, found
399.1831.
5816 J. Org. Chem. Vol. 75, No. 17, 2010

Liu et al.
6,7-Dimethoxy-1-(2-((4-methoxyphenyl)ethynyl)phenyl)-1,2,3,4-
JOCArticle
1-(2-((4-Fluorophenyl)ethynyl)phenyl)-2,3,4,9-tetrahydro-1H-
pyrido[3,4-b]indole (3q): 1H NMR (300 MHz, CDCl3) δ 7.99 (s,
1H), 7.53 (d, J = 8.1 Hz, 1H), 7.67-7.64 (m, 1H), 7.55 (d, J =
7.2 Hz, 3H), 7.15 (t, J = 8.1 Hz, 3H), 7.08-6.96 (m, 3H), 5.70 (s,
1H), 4.01 (br s, 1H), 3.54 (br s, 1H), 2.94 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 155.2 144.1 140.0 136.2 136.1 133.5 132.7 132.0
129.4 128.8 127.4 126.5 122.1 122.0 119.5 118.3 115.9 111.0 110.9
109.4 87.3 80.2 60.2 41.0 21.0; MS (EI, m/z) 366 [M]þ; HRMS
(EI) calcd for C25H19FN2 [M]þ 366.1532, found 366.1542.
1-(2-(m-Tolylethynyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido-
tetrahydroisoquinoline (3j): 1H NMR (300 MHz, CDCl3) δ 7.52
(d, J = 8.1 Hz, 1H), 7.45 (d, J = 7.2 Hz, 1H), 7.35 (d, J = 7.2
Hz, 1H), 7.21 (t, J = 7.2 Hz, 2H), 6.98 (t, J = 7.8 Hz, 1H), 6.91
(t, J = 7.2 Hz, 2H), 6.63 (s, 2H), 5.83 (s, 1H), 4.16 (br s, 1H),
3.85 (s, 4H), 3.72 (s, 5H), 3.35 (br s, 1H), 2.75 (br, 2H); 13C
NMR (75 MHz, CDCl3) δ 154.4 147.8 147.5 140.5 138.7 135.6
133.7 131.7 130.4 130.2 128.1 124.8 124.6 124.2 118.8 115.6
114.8 111.0 100.3 80.4 60.6 59.7 55.6 42.0 27.3; MS (EI, m/z)
399 [M]þ; HRMS (EI) calcd for C26H25NO3 [M]þ 399.1834,
found 399.1840.
1
[3,4-b]indole (3r): H NMR (300 MHz, CDCl3) δ 7.93 (s, 1H),
1-(2-((4-Fluorophenyl)ethynyl)phenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (3k): 1H NMR (300 MHz, CDCl3) δ 7.70
(s, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.27-7.20 (m, 3H), 7.07-7.01
(m, 1H), 6.93 (t, J = 7.8 Hz, 2H), 6.65 (s, 2H), 5.63 (s, 1H), 4.14
(br s,1H), 3.87 (s, 3H), 3.74 (s, 3H), 3.37 (br s, 1H), 2.94 (br, 1H),
2.79 (br, 1H); 13C NMR (75 MHz, CDCl3) δ 155.5 147.7 147.3
140.0 138.8 135.0 128.7 128.2 128.0 127.5 127.1 126.7 113.1 111.1
110.6 100.2 80.2 61.4 55.8 55.7 41.1 28.4; MS (EI, m/z) 387 [M]þ;
HRMS (EI) calcd for C25H22FNO2 [M]þ 387.1635, found
387.1637.
1-(2-((4-Chlorophenyl)ethynyl)phenyl)-6,7-dimethoxy-1,2,3,4-
tetrahydroisoquinoline (3l): 1H NMR (300 MHz, CDCl3) δ 7.51
(d, J = 7.8 Hz, 1H), 7.29 (d, J = 8.4 Hz, 1H), 7.21 (t, J = 7.2 Hz,
3H), 7.02 (br s, 1H), 6.91 (t, J = 7.8 Hz, 2H), 6.64 (s, 2H), 5.92
(s, 1H), 4.16 (br s, 1H), 3.85 (s, 3H), 3.72 (s, 3H), 3.36 (br s, 1H),
2.92-2.89 (m, 1H), 2.78-2.73 (br, 1H); 13C NMR (75 MHz,
CDCl3) δ 147.8 147.4 138.8 134.0 130.4 130.0 129.3 128.9 128.4
128.0 127.4 126.5 125.0 124.4 118.9 116.0 111.4 111.1 100.3 80.3
61.6 55.8 55.7 40.0 28.0; MS (EI, m/z) 403 [M]þ; HRMS (EI)
calcd for C25H22ClNO2 [M]þ 403.1339, found 403.1342.
1-(2-(Pent-1-ynyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (3m): 1H NMR (300 MHz, CDCl3) δ 7.59-7.54 (m, 3H),
7.36-7.33 (m, 2H), 7.16-7.12 (m, 3H), 6.01 (s, 1H), 4.20 (br s,
1H), 3.71 (br s, 1H), 299 (br s, 2H), 1.85 (t, J = 7.2 Hz, 2H), 1.01
(t, J = 7.2 Hz, 3H), 0.88-0.80 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 136.2 134.5 132.4 131.6 128.6 128.3 127.9 126.7 126.5
126.4 123.3 93.6 80.1 61.9 44.1 29.2 24.1 22.0 17.6; MS (EI, m/z)
314 [M]þ; HRMS (EI) calcd for C22H22N2 [M]þ 314.1783, found
314.1785.
1-(2-(5-Chloropent-1-ynyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido-
[3,4-b]indole (3n): 1H NMR (300 MHz, CDCl3) δ 7.67-7.64 (m,
1H), 7.56 (s, 1H), 7.45 (d, J = 7.8 Hz, 1H), 7.30-7.27 (m, 4H),
7.00 (t, J = 8.1 Hz, 1H), 5.90 (s, 1H), 4.30-4.21 (br, 2H), 3.69 (t,
J = 6.3 Hz, 2H), 2.97 (s, 2H), 2.66 (t, J = 6.9 Hz, 2H), 2.10-2.04
(m, 2H); 13C NMR (75 MHz, DMSO) δ 146.0 140.6 136.6 132.5
131.9 130.4 129.3 128.6 126.7 122.0 119.3 118.5 112.0 109.2 100.3
80.4 60.0 48.6 44.4 32.0 31.4 30.6; MS (EI, m/z) 348 [M]þ;
HRMS (EI) calcd for C22H21ClN2 [M]þ 348.1393, found
348.1396.
1-(2-(Phenylethynyl)phenyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]-
indole (3o): 1H NMR (300 MHz, CDCl3) δ 7.56-7.54 (m, 3H),
7.37-7.34 (m, 3H), 7.30-7.27 (m, 3H), 7.15-7.10 (m, 3H), 6.99
(t, J = 7.8 Hz, 1H), 5.89 (s, 1H), 4.08- 3.85 (br, 1H), 3.25 (br s,
1H), 2.64 (s, 2H); 13C NMR (75 MHz, CDCl3) δ 146.2 140.0
136.2 132.8 132.0 131.5 129.4 128.8 128.5 127.3 126.4 122.1 121.9
119.6 119.4 118.2 118.2 111.0 110.9 87.6 81.0 60.0 42.3 24.5; MS
(EI, m/z) 348 [M]þ; HRMS (EI) calcd for C25H20N2 [M]þ
348.1626, found 348.1632.
7.66 (d, J = 7.2 Hz, 1H), 7.46 (d, J = 7.5 Hz, 3H), 7.19-7.11 (m,
6H), 7.00 (t, J = 7.5 Hz, 1H), 5.98 (s, 1H), 4.19-3.99 (br, 1H),
3.22 (br s, 1H), 2.69 (s, 2H), 2.19 (s, 3H); 13C NMR (75 MHz,
DMSO) δ 137.0 136.9 134.0 132.8 131.9 130.6 129.0 128.9 128.6
128.4 128.3 126.4 125.3 123.0 115.5 115.1 114.9 114.0 113.9 113.1
94.8 82.4 60.0 47.6 32.1 28.1; MS (EI, m/z) 362[M]þ; HRMS (EI)
calcd for C26H22N2 [M]þ 362.1783, found 362.1780.
7-Methyl-1-(2-(phenylethynyl)phenyl)-1,2,3,4-tetrahydroiso-
quinoline (3s): 1H NMR (300 MHz, CDCl3) δ 7.66 (d, J = 7.5
Hz, 2H), 7.44 (s, 1H), 7.22-7.20 (m, 4H), 7.14 (d, J = 7.5 Hz,
3H), 6.92 (t, J = 7.2 Hz, 2H), 6.11 (s, 1H), 3.38 (br s, 2H), 2.92 (s,
2H), 2.17(s, 3H); 13C NMR (75 MHz, CDCl3) δ 147.2 139.6
136.2 135.3 135.0 128.7 128.6 128.4 128.0 126 126.3 100.7 80.4
61.9 40.0 29.5 22.1; MS (EI, m/z) 323 [M]þ; HRMS (EI) calcd for
C24H21N [M]þ 323.1674, found 323.1678.
7-(2-(Phenylethynyl)phenyl)-4,5,6,7-tetrahydrothieno[2,3-c]-
pyridine (3t): 1H NMR (300 MHz, CDCl3) δ 7.70-7.54 (m, 1H),
7.53 (d, J = 7.2 Hz, 2H), 7.36 (d, J = 7.2 Hz, 2H), 7.21 (t, J =
7.2 Hz, 2H), 6.98 (t, J = 6.9 Hz, 1H), 6.91 (t, J = 7.5 Hz, 2H),
6.81 (d, J = 6.9 Hz, 1H), 6.07 (s, 1H), 3.63 (br, 2H), 2.92-2.90
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 136.2 132.0 129.4 128.8
128.6 128.5 128.4 128.3 126.4 125.6 123.7 122.1 119.5 118.2 111.0
100.1 80.5 65.5 44.3 29.1; MS (EI, m/z) 315 [M]þ; HRMS (EI)
calcd for C21H17NS [M]þ 315.1082, found 315.1087.
7-Methoxy-1-(2-(phenylethynyl)phenyl)-1,2,3,4-tetrahydroiso-
quinoline (3u): 1H NMR(300 MHz, CDCl3) δ7.89 (d, J = 6.9Hz,
1H), 7.80 (d, J = 7.2 Hz, 1H), 7.71-7.67 (m, 1H), 7.45 (d, J =
7.2 Hz, 1H), 7.37-7.33 (m, 2H), 7.21 (t, J = 7.5 Hz, 2H), 6.99 (t,
J = 6.9 Hz, 1H), 6.92 (t, J = 7.2 Hz, 2H), 6.75 (s, 1H), 6.08 (s,
1H), 4.15 (br, 1H), 3.85 (s, 3H), 3.36 (br, 1H), 2.92-2.88 (m,
1H), 2.78 (br, 1H); 13C NMR (75 MHz, CDCl3) δ 158.1 150.4
150.0 146.0 144.0 139.1 135.7 135.1 133.3 131.4 130.7 130.4 128.2
125.9 122.1 121.9 119.0 116.0 96.1 94.0 61.0 55.8 41.2 28.0; MS
(EI, m/z) 339 [M]þ; HRMS (EI) calcd for C24H21NO [M]þ
339.1623, found 339.1630.
Typical Procedure for the Synthesis of 8-Phenyl-5,6-dihydro-
isoquinolino[1,2-a]isoquinolizinium Hexafluorostilbate (2a). A
mixture of 1a (0.1 mmol) and AgSbF6 (0.1 mmol)/AuCl(PPh3)
(0.01 mmol) in 5 mL of anhydrous toluene was heated at 110 °C
in a sealed tube for 12 h. After the reaction was cooled to
ambient temperature, the solvent was removed under reduced
pressure. The residue was purified by column chromatography
with CH2Cl2/MeOH (20/1, v/v) to yield 2a as a yellow solid
(yield 76%): 1H NMR (300 MHz, CDCl3) δ 8.48 (d, J = 8.7 Hz,
1H), 8.08 (t, J = 7.5 Hz, 2H), 8.00 (s, 1H), 7.95 (d, J = 8.1 Hz,
1H), 7.88 (t, J = 7.2 Hz, 2H), 7.72 (d, J = 7.2 Hz, 2H), 7.60 (t, J
= 7.2 Hz, 3H), 7.48 (d, J = 7.2 Hz, 2H), 4.69 (s, 2H), 3.53 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 154.8 148.2 139.0 138.3
136.1 134.0 133.2 132.2 131.0 129.8 128.5 128.4 128.0 126.5 125.9
46.0 27.5; MS (EI, m/z) 308 [M]þ; HRMS (EI) calcd for
C23H18N [M]þ 308.1434, found 308.1438.
1-(2-((4-Methoxyphenyl)ethynyl)phenyl)-2,3,4,9-tetrahydro-
1H-pyrido[3,4-b]indole (3p): 1H NMR (300 MHz,CDCl3) δ 7.65-
7.62 (m, 1H), 7.55-7.49 (m, 5H), 7.24 (s, 1H), 7.15-7.10 (m, 2H),
6.83 (d, J = 8.7 Hz, 3H), 5.82 (s, 1H), 4.22 (br s, 1H), 3.84 (s, 3H),
3.62 (br s, 1H), 2.96 (s, 2H); 13C NMR (75 MHz, DMSO) δ 159.5
155.0 140.0 136.2 133.2 132.6 132.4 131.4 128.7 127.9 126.3 128.2
121.2 118.6 117.8 114.6 114.1 111.4 108.6 94.3 86.3 79.3 55.2 46.2
28.0; MS (EI, m/z) 378 [M]þ; HRMS (EI) calcd for C26H22N2O
[M]þ 378.1732, found 378.1738.
8-Propyl-5,6-dihydroisoquinolino[1,2-a]isoquinolizinium Hex-
afluorostilbate (2c). In the same manner as described in the
preparation of 2a, 2c was obtained as a yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 71%): 1H NMR (300 MHz, CDCl3) δ8.47 (d, J=
8.7 Hz, 1H), 8.10-8.05 (m, 2H), 7.95 (s, 1H), 7.86 (d, J = 7.8 Hz,
J. Org. Chem. Vol. 75, No. 17, 2010 5817

Liu et al.
JOCArticle
1H), 7.82 (d, J = 6.9 Hz, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.59 (t,
J = 7.8 Hz, 2H), 3.44 (t, J = 5.7 Hz, 2H), 3.35 (t, J = 6.0 Hz,
2H), 1,80-1.66 (m, 4H), 1.20 (br s, 3H); 13C NMR (75 MHz,
CDCl3) δ 154.4 147.1 139.4 138.8 135.7 133.9 132.7 130.3 130.0
128.3 127.4 127.3 126.6 125.4 124.5 50.0 41.4 37.0 32.9 25.9; MS
(EI, m/z) 274 [M]þ; HRMS (EI) calcd for C20H20N [M]þ
274.1590, found 274.1593.
8-Isobutyl-5,6-dihydroisoquinolino[1,2-a]isoquinolizinium hex-
afluorostilbate (2d). In the same manner as described in the pre-
paration of 2a, 2d was obtained as a yellow solid after purifica-
tion by column chromatography with CH2Cl2/MeOH (20/1, v/v)
(yield 63%): 1H NMR (300 MHz, CDCl3) δ 8.46 (d, J = 6.3 Hz,
1H), 8.08 (d, J = 6.0 Hz, 1H), 8.03 (t, J = 5.1 Hz, 1H), 7.96 (s,
1H), 7.83 (t, J = 5.7 Hz, 2H), 7.67 (t, J = 5.4 Hz, 1H), 7.61 (d,
J = 5.4 Hz, 1H), 7.53 (t, J = 6.0 Hz, 1H), 3.55 (s, 2H), 3.49 (d,
J = 4.8 Hz, 2H), 1.69 (s, 2H), 1.09 (s, 3H), 1.08 (s, 3H), 0.89-
0.83 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 154.4 148.0 139.9
138.9 135.4 133.8 132.5 130.1 128.4 127.4 127.2 126.6 125.3 124.5
53.4 50.5 42.9 30.9 27.9 27.7; MS (EI, m/z) 288 [M]þ; HRMS (EI)
calcd for C21H22N [M]þ 288.1747, found 288.1751.
135.5 133.8 133.2 130.9 130.3 129.8 129.7 129.3 128.6 128.1 127.6
126.7 126.3 126.1 125.9 125.2 52.1 31.1 29.6 27.6; MS (ESI, m/z)
364 [M]þ; HRMS (ESI) calcd for C27H26N [M]þ 364.2060,
found 364.2057.
8-(4-Fluorophenyl)-5,6-dihydroisoquinolino[1,2-a]isoquinoliz-
inium Hexafluorostilbate (2i). In the same manner as described in
the preparation of 2a, 2i was obtained as yellow solid after
purification by column chromatography with CH2Cl2/MeOH
1
(20/1, v/v) (yield 70%): H NMR (300 MHz, CDCl3) δ 8.61 (d,
J = 8.4 Hz, 1H), 8.06 (s, 1H), 7.92 (t, J = 8.4 Hz, 2H), 7.78 (t,
J = 7.5 Hz, 2H), 7.62-7.50 (m, 7H), 3.79 (d, J = 5.8 Hz, 2H), 3.39
(d, J = 6.0 Hz, 2H); 13C NMR (75 MHz, DMSO) δ 164.1 156.1
147.1 144.1 135.8 133.7 133.0 130.8 130.2 130.1 130.0 129.2 128.2
127.5 126.7 125.9 119.5 56.1 28.0; MS (ESI, m/z) 326 [M]þ; HRMS
(ESI) calcd for C23H17FN [M]þ 326.1340, found 326.1334.
8-(4-Chlorophenyl)-5,6-dihydroisoquinolino[1,2-a]isoquinoliz-
inium Hexafluorostilbate (2j). In the same manner as described in
the preparation of 2a, 2j was obtained as yellow solid after
purification by column chromatography with CH2Cl2/MeOH
1
(20/1, v/v) (yield 62%): H NMR (300 MHz, CDCl3) δ 8.50 (d,
8-(3-Chloropropyl)-5,6-dihydroisoquinolino[1,2-a]isoquinolizinium
Hexafluorostilbate (2e). In the same manner as described in the
preparation of 2a, 2e was obtained as a yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 58%): 1H NMR (300 MHz, CDCl3) δ 8.49 (d,
J = 8.7 Hz, 1H), 8.10 (d, J = 7.5 Hz, 1H), 7.87 (d, J = 8.7 Hz,
2H), 7.66 (d, J = 7.2 Hz, 1H), 7.59 (d, J = 7.8 Hz, 2H), 7.59 (d,
J = 7.8 Hz, 2H), 3.82 (t, J = 5.7 Hz, 2H), 3.60 (t, J = 7.5 Hz,
2H), 3.40 (t, J = 5.7 Hz, 2H), 2.42 (t, J = 6.9 Hz, 2H), 2.29-2.18
(m, 2H); 13C NMR (75 MHz, CDCl3) δ 148.2 146.0 141.1 137.9
135.6 130.6 128.5 127.2 127.1 126.8 123.9 122.3 121.3 57.1 47.1
32.0 28.2 25.1; MS (ESI, m/z) 308 [M]þ; HRMS (ESI) calcd for
C20H19ClN [M]þ 308.1201, found 308.1196.
8-(Cyclohexylmethyl)-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (2f). In the same manner as des-
cribed in the preparation of 2a, 2f was obtained as a yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 65%): 1H NMR (300 MHz, CDCl3) δ
8.50 (d, J = 8.7 Hz, 1H), 8.09 (s, 1H), 7.95 (d, J = 8.1 Hz, 1H),
7.89 (t, J = 7.2 Hz, 2H), 7.72 (t, J = 6.6 Hz, 1H), 7.60 (t, J = 6.3
Hz, 2H), 7.49 (d, J = 7.2 Hz, 1H), 4.75 (t, J = 6.0 Hz, 2H), 3.53
(t, J = 7.0 Hz, 2H), 2.93 (d, J = 6.5 Hz, 2H), 2.09-1.94 (m, 1H),
1.19-1.14 (m, 4H), 1.07-0.98 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ 147.3 140.4 139.2 138.4 136.0 134.1 133.0 130.5 130.1
129.6 129.0 128.1 126.8 126.5 124.6 49.0 43.6 35.1 29.7 29.0 27.3
21.5 19.1; MS (EI, m/z) 328 [M]þ; HRMS (EI) calcd for
C24H26N [M]þ 328.2060, found 328.2070.
8-p-Tolyl-5,6-dihydroisoquinolino[1,2-a]isoquinolizinium Hex-
afluorostilbate (2g). In the same manner as described in the
preparation of 2a, 2g was obtained as a yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 70%): 1H NMR (300 MHz, CDCl3) δ 8.54 (d,
J = 8.7 Hz, 1H), 8.17 (t, J = 8.1 Hz, 1H), 8.00 (s, 1H), 7.98 (d,
J = 7.5 Hz, 1H), 7.87 (t, J = 8.7 Hz, 1H), 7.70-7,62 (m, 4H),
7.56 (t, J = 6.9 Hz, 2H), 7.38 (d, J = 7.8 Hz, 2H), 4.65 (t, J = 5.7
Hz, 2H), 3.28 (t, J = 6.0 Hz, 2H), 2.42 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 154.4 146.7 141.2 138.9 135.8 133.8 133.0 130.8
130.3 130.2 130.1 129.3 128.3 127.5 126.7 125.9 125.1 52.2 27.8
21.5; MS (EI, m/z) 322 [M]þ; HRMS (EI) calcd for C24H20N
[M]þ 322.1590, found 322.1597.
8-(4-tert-Butylphenyl)-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (2h). In the same manner as de-
scribed in the preparation of 2a, 2h was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 56%): 1H NMR (300 MHz, CDCl3) δ
8.59 (d, J = 6.6 Hz, 1H), 8.16-8.01 (m, 4H), 7.89 (t, J = 6.0 Hz,
2H), 7.68-7.54 (m, 6H), 4.59 (s, 2H), 3.22 (s, 2H), 1.38 (s, 9H);
13C NMR (75 MHz, CDCl3) δ 154.5 154.3 146.4 138.8 138. Six
J = 6.6 Hz, 1H), 8.08 (t, J = 6.3 Hz, 2H), 8.00 (s, 1H), 7.95 (d,
J = 6.0 Hz, 1H), 7.96 (d, J = 6.0 Hz, 2H), 7.72 (t, J = 5.4 Hz, 1H),
7.60 (t, J = 5.7 Hz, 3H), 7.53 (d, J = 2.4 Hz, 2H), 3.31 (s, 2H), 3.26
(d, J = 5.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 159.1 155.1
147.1 144.1 135.8 133.7 133.0 130.8 130.2 130.1 130.0 129.2 128.2
127.5 126.7 125.8 122.5 56.4 28.1; MS (ESI, m/z) 342 [M]þ; HRMS
(ESI) calcd for C23H17ClN [M]þ 342.1044, found 342.1044.
8-(2-Methoxyphenyl)-5,6-dihydroisoquinolino[1,2-a]isoquinoliz-
inium Hexafluorostilbate (2k). In the same manner as described
in the preparation of 2a, 2k was obtained as yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 74%): 1H NMR (300 MHz, CDCl3) δ 8.59 (d,
J = 6.0 Hz, 1H), 8.18 (d, J = 6.3 Hz, 1H), 8.11 (t, J = 6.3 Hz,
2H), 8.01 (d, J = 6.0 Hz, 1H), 7.93 (t, J = 6.3 Hz, 1H), 7.73-
7.56 (m, 5H), 7.12 (d, J = 6.9 Hz, 2H), 4.65 (t, J = 4.7 Hz, 2H),
3.90 (s, 3H), 3.21 (t, J = 4.5 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 159.5 151.1 145.4 138.8 138.4 136.0 133.9 132.9 131.6
130.9 130.2 128.1 127.7 126.5 125.8 124.9 124.0 115.8 56.1 51.9
27.6; MS (EI, m/z) 338 [M]þ; HRMS (EI) calcd for C24H20NO
[M]þ 338.1539, found 338.1536.
8-(3-Methoxyphenyl)-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (2l). In the same manner as de-
scribed in the preparation of 2a, 2l was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 70%): 1H NMR (300 MHz, CDCl3) δ
8.58 (d, J = 6.0 Hz, 1H), 8.18 (d, J = 6.3 Hz, 1H), 8.11 (t, J =
6.6 Hz, 2H), 8.00 (d, J = 5.7 Hz, 1H), 7.93 (t, J = 5.7 Hz, 1H),
7.72 (t, J = 5.7 Hz, 1H), 7.67-7.61 (m, 3H), 7.57 (d, J = 5.4 Hz,
1H), 7.11 (d, J = 6.6 Hz, 2H), 4.65 (t, J = 4.5 Hz, 2H), 3.90 (s,
3H), 3.20 (t, J = 4.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
165.6 156.4 148.4 138.6 138.4 136.0 133.9 132.9 131.5 130.9
130.2 128.1 127.7 126.5 125.8 124.9 124.0 110.8 55.5 51.9 27.6;
MS (EI, m/z) 338 [M]þ; HRMS (EI) calcd for C24H20NO [M]þ
338.1539, found 338.1540.
8-(4-Methoxyphenyl)-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (2m). In the same manner as de-
scribed in the preparation of 2a, 2m was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 75%): 1H NMR (300 MHz, CDCl3) δ
8.59 (d, J = 6.3 Hz, 1H), 8.18 (d, J = 6.0 Hz, 1H), 8.11 (t, J =
6.6 Hz, 2H), 8.10 (d, J = 5.7 Hz, 1H), 7.93 (t, J = 5.4 Hz, 1H),
7.71 (t, J = 5.4 Hz, 1H), 7.67-7.61 (m, 3H), 7.57 (d, J = 5.7 Hz,
1H), 7.12 (d, J = 6.6 Hz, 2H), 4.65 (t, J = 4.2 Hz, 2H), 3.90 (s,
3H), 3.20 (t, J = 4.8 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
161.6 154.4 146.4 138.8 138.4 136.0 133.9 132.9 131.6 130.9 130.2
128.1 127.7 126.5 125.8 124.9 124.0 114.8 55.5 51.9 27.6; MS (EI,
m/z) 338 [M]þ; HRMS (EI) calcd for C24H20NO [M]þ 338.1539,
found 338.1534.
5818 J. Org. Chem. Vol. 75, No. 17, 2010

Liu et al.
2,3-Dimethoxy-8-propyl-5,6-dihydroisoquinolino[1,2-a]isoquino-
JOCArticle
scribed in the preparation of 2a, 4g was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 64%): 1H NMR (300 MHz, CDCl3) δ
8.62 (d, J = 6.6 Hz, 1H), 8.12-8.06 (m, 2H), 7.94 (s, 1H), 7.90 (t,
J = 6.3 Hz, 1H), 7.61 (d, J = 6.3 Hz, 2H), 7.46 (s, 1H), 7.41 (d,
J = 5.7 Hz, 2H), 7.15 (s, 1H), 4.62 (t, J = 4.5 Hz, 2H), 4.06 (s,
3H), 3.96 (s, 3H), 3.23 (t, J = 4.8 Hz, 2H), 2.48 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 154.5 148.4 146.4 141.4 138.7 135.5
133.7 130.4 130.3 130.0 129.8 128.3 128.0 124.8 124.3 118.8 115.9
111.0 56.7 56.6 51.8 29.2 27.2; MS (EI, m/z) 382 [M]þ; HRMS
(EI) calcd for C26H24NO2 [M]þ 382.1802, found 382.1823.
2,3-Dimethoxy-8-(2-methoxyphenyl)-5,6-dihydroisoquinolino-
[1,2-a]isoquinolizinium Hexafluorostilbate (4h). In the same
manner as described in the preparation of 2a, 4h was obtained
as yellow solid after purification by column chromatography
with CH2Cl2/MeOH (20/1, v/v) (yield 83%): 1H NMR (300
MHz, CDCl3) δ 8.66 (d, J = 6.6 Hz, 1H), 8.17-8.12 (m, 2H),
7.98-7.95 (m, 2H), 7.64 (t, J = 6.0 Hz, 1H), 7.50 (d, J = 6.0 Hz,
1H), 7.46 (s, 1H), 7.33 (s, 1H), 7.23 (t, J = 5.7 Hz, 1H), 7.12 (d,
J = 6.2 Hz, 1H), 4.51 (s, 1H), 4.43 (s, 1H), 4.10 (s, 3H), 3.98 (s,
3H), 3.83 (s, 3H), 3.31 (t, J = 4.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 156.9 154.7 153.9 148.3 143.6 138.8 135.7 134.4 133.3
131.3 130.7 130.3 128.1 124.8 121.8 120.9 118.4 115.4 111.4 111.2
56.8 56.6 55.8 50.4 26.8; MS (EI, m/z) 398 [M]þ; HRMS (EI)
calcd for C26H24NO3 [M]þ 398.1751, found 398.1747.
lizinium Hexafluorostilbate (4a). In the same manner as de-
scribed in the preparation of 2a, 4a was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 71%): 1H NMR (300 MHz, CDCl3) δ
8.07 (t, J = 8.4 Hz, 1H), 7.93 (s, 1H), 7.74 (d, J = 6.6 Hz, 1H),
7.64 (d, J = 5.7 Hz, 1H), 7.42 (d, J = 6.6 Hz, 1H), 7.30 (s, 1H),
7.15 (s, 1H), 4.02 (d, J = 6.6 Hz, 2H), 3.95 (s, 3H), 3.92 (s, 3H),
3.42 (t, J = 3.0 Hz, 2H), 2.45 (t, J = 8.0 Hz, 2H), 1.27-1.14 (m,
2H), 0.79 (t, J = 7.5 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
154.2 148.6 148.1 147.6 138.9 135.4 134.0 130.4 129.8 127.5 124.1
122.5 118.5 115.4 110.8 56.6 56.5 49.2 35.3 27.1 21.4 13.7; MS
(EI, m/z) 334 [M]þ; HRMS (EI) calcd for C22H24NO2 [M]þ
334.1802, found 334.1790.
8-Hexyl-2,3-dimethoxy-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (4b). In the same manner as de-
scribed in the preparation of 2a, 4b was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 74%): 1H NMR (300 MHz, CDCl3) δ
8.02 (d, J = 7.5 Hz, 1H), 7.87 (s, 1H), 7.65 (d, J = 7.5 Hz, 1H),
7.64-7.47 (m, 2H), 7.30 (s, 1H), 7.13 (s, 1H), 4.01 (s, 2H), 3.94 (s,
3H), 3.92 (s, 3H), 3.39 (t, J = 6.3 Hz, 2H), 2.80 (t, J = 5.7 Hz,
2H), 1.54-1.35 (m, 8H), 0.90 (t, J = 3.0 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 154.2 148.1 147.9 147.3 138.9 135.3 134.0 130.7
129.9 127.4 124.1 122.3 118.6 115.4 56.5 56.0 49.1 33.4 31.5 28.1
27.1 25.7 22.4 14.0; MS (EI, m/z) 376 [M]þ; HRMS (EI) calcd for
C25H30NO2 [M]þ 376.2271, found376.2284.
8-Isobutyl-2,3-dimethoxy-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (4c). In the same manner as de-
scribed in the preparation of 2a, 4c was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
MeOH (20/1, v/v) (yield 67%): 1H NMR (300 MHz, CDCl3) δ
8.51(d, J = 8.4 Hz, 1H), 8.08-8.01 (m, 2H), 7.86-7.81 (m, 2H),
7.31(s, 1H), 7.17 (s, 1H), 4.07 (s, 3H), 3.93 (s, 3H), 3.46 (t, J = 6.6
Hz, 2H), 3.37 (d, J = 6.7 Hz, 2H), 2.21-2.15 (m, 3H), 1.12 (s,
3H), 1.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 154.3 148.1
146.9 138.7 135.4 134.3 129.9 129.8 127.4 124.2 123.9 118.6 115.4
110.9 56.6 56.5 49.7 42.7 29.2 27.7 27.3 22.4; MS (EI, m/z) 348
[M]þ; HRMS (EI) calcd for C23H26NO2 [M]þ 348.1958, found
348.1962.
2,3-Dimethoxy-8-(3-methoxyphenyl)-5,6-dihydroisoquinolino-
[1,2-a]isoquinolizinium Hexafluorostilbate (4i). In the same man-
ner as described in the preparation of 2a, 4i was obtained as
yellow solid after purification by column chromatography with
1
CH2Cl2/MeOH (20/1, v/v) (yield 80%): H NMR (300 MHz,
CDCl3) δ 8.59 (d, J = 9.0 Hz, 1H), 8.11-8.01 (m, 2H), 7.92 (s,
1H), 7.87 (t, J = 8.1 Hz, 1H), 7.46 (t, J = 6.3 Hz, 2H), 7.36 (s,
1H), 7.18 (d, J = 6.9 Hz, 2H), 7.09 (d, J = 6.6 Hz, 1H), 4.58 (br s,
2H), 4.03 (s, 3H), 3.95 (s, 3H), 3.90 (s, 3H), 3.24 (br s, 2H); 13
C
NMR (75 MHz, CDCl3) δ 160.0 154.5 154.3 148.2 145.9 138.6
135.4 133.8 133.5 130.3 128.1 125.0 124.3 121.8 118.8 117.3 115.9
114.9 111.1 56.8 56.7 56.0 51.8 27.2; MS (ESI, m/z) 398 [M]þ;
HRMS (ESI) calcd for C26H24NO3 [M]þ 398.1751, found
398.1766
2,3-Dimethoxy-8-(4-methoxyphenyl)-5,6-dihydroisoquinolino-
[1,2-a]isoquinolizinium Hexafluorostilbate (4j). In the same man-
ner as described in the preparation of 2a, 4j was obtained as
yellow solid after purification by column chromatography with
8-(Cyclohexylmethyl)-2,3-dimethoxy-5,6-dihydroisoquinolino-
[1,2-a]isoquinolizinium Hexafluorostilbate (4e). In the same man-
ner as described in the preparation of 2a, 4e was obtained as
yellow solid after purification by column chromatography with
1
CH2Cl2/MeOH (20/1, v/v) (yield 84%). H NMR (300 MHz,
1
CH2Cl2/MeOH (20/1, v/v) (yield 72%): H NMR (300 MHz,
CDCl3) δ 8.56 (d, J = 6.6 Hz, 1H), 8.02-8.10 (dd, J = 12.9 Hz,
J = 5.7 Hz, 2H), 7.93 (s, 1H), 7.84 (t, J = 5.4 Hz, 1H), 7.67 (br s,
2H), 7.42 (s, 1H), 7.11-7.06 (m, 3H), 4.62 (s, 2H), 4.00 (s, 3H),
3.91 (s, 3H), 3.84 (s, 3H), 3.21 (s, 2H); 13C NMR (75 MHz,
CDCl3) δ 161.5 154.3 148.3 146.2 138.7 135.5 133.6 131.6 130.4
130.1 128.0 124.7 124.5 124.2 118.8 115.6 114.8 110.9 56.6 55.5
53.7 51.5 27.2; MS (EI, m/z) 398 [M]þ; HRMS (EI) calcd for
C26H24NO3 [M]þ 398.1751, found 398.1725.
8-(4-Fluorophenyl)-2,3-dimethoxy-5,6-dihydroisoquinolino[1,2-a]-
isoquinolizinium Hexafluorostilbate (4k). In the same manner as
described in the preparation of 2a, 4k was obtained as yellow
solid after purification by column chromatography with
CDCl3) δ 8.50 (d, J = 9.0 Hz, 1H), 8.03 (m, 2H), 7.86-7.81 (m,
2H), 7.31 (s, 1H), 7.19 (s, 1H), 4.07 (s, 3H), 4.01 (s, 1H), 3.97 (s,
1H), 3.96 (s, 3H), 3.44 (d, J = 6.6 Hz, 2H), 3.40 (d, J = 5.1 Hz,
2H), 1.82-1.58 (m, 11H); 13C NMR (75 MHz, CDCl3) δ 154.3
148.1 146.2 138.6 135.4 134.1 129.9 128.0 127.4 124.2 124.1 118.5
115.3 110.8 56.6 56.5 49.6 41.4 36.9 33.3 32.9 27.1 25.9; MS (EI,
m/z) 388 [M]þ; HRMS (EI) calcd for C26H30NO2 [M]þ
388.2271, found 388.2280.
8-(4-tert-Butylphenyl)-2,3-dimethoxy-5,6-dihydroisoquinolino-
[1,2-a]isoquinolizinium Hexafluorostilbate (4f). In the same man-
ner as described in the preparation of 2a, 4f was obtained as
yellow solid after purification by column chromatography with
1
CH2Cl2/MeOH (20/1, v/v) (yield 72%): H NMR (300 MHz,
1
CH2Cl2/MeOH (20/1, v/v) (yield 74%): H NMR (300 MHz,
CDCl3) δ 8.56 (d, J = 6.2 Hz, 1H), 7.90 (d, J = 6.0 Hz, 1H), 7.50
(s, 1H), 7.50-7.33 (m, 5H), 7.20 (t, J = 5.1 Hz, 2H),7.10 (t, J =
6.0 Hz, 1H), 4.06 (s, 2H), 3.97 (s, 6H), 3.89 (s, 2H); 13C NMR (75
MHz, CDCl3) δ 154.3 148.3 145.2 138.6 135.5 134.2 133.4 132.6
132.5 130.4 130.3 128.4 128.1 125.0 124.6 118.9 116.7 116.4 115.9
110.6 56.6 56.5 51.6 27.2; MS (EI, m/z) 386 [M]þ; HRMS (EI)
calcd for C25H21FNO2 [M]þ 386.1551, found 386.1543.
8-(4-Chlorophenyl)-2,3-dimethoxy-5,6-dihydroisoquinolino[1,2-a]-
isoquinolizinium Hexafluorostilbate (4l). In the same manner as
described in the preparation of 2a, 4l was obtained as yellow
solid after purification by column chromatography with
CDCl3) δ 8.09 (d, J = 7.5 Hz, 1H), 7.94 (d, J = 7.2 Hz, 1H), 7.65
(d, J = 4.5 Hz, 4H), 7.47 (s, 1H), 7.33-7.29 (m, 3H), 7.19 (s,
1H), 4.08 (s, 3H), 3.97 (s, 3H), 3.88 (s, 2H), 3.64 (s, 2H), 1.40 (s,
9H); 13C NMR (75 MHz, CDCl3) δ 154.5 138.7 135.5 133.7
131.3 130.3 129.7 128.2 128.0 126.4 124.9 124.6 124.4 118.8 115.8
111.0 110.2 56.7 51.7 31.1 29.6 27.2; MS (ESI, m/z) 424 [M]þ;
HRMS (ESI) calcd for C29H30NO2 [M]þ 424.2271, found
424.2269.
2,3-Dimethoxy-8-p-tolyl-5,6-dihydroisoquinolino[1,2-a]isoqui-
nolizinium Hexafluorostilbate (4g). In the same manner as de-
J. Org. Chem. Vol. 75, No. 17, 2010 5819

Liu et al.
JOCArticle
1
CH2Cl2/MeOH (20/1, v/v) (yield 76%): H NMR (300 MHz,
CDCl3) δ 7.60 (d, J = 6.3 Hz, 2H), 7.42 (d, J = 6.6 Hz, 2H),
7.23-7.03 (m, 5H), 7.02 (d, J = 5.7 Hz, 2H), 3.82 (s, 6H), 3.19 (t,
J = 4.8 Hz, 2H), 3.12 (t, J = 4.2 Hz, 2H); 13C NMR (75 MHz,
CDCl3) δ 154.5 146.5 138.7 135.5 133.8 130.4 129.7 128.3 128.8
128.4 128.0 127.3 126.4 125.0 124.4 118.8 115.9 111.4 111.1 56.7
55.8 41.8 29.3; MS (ESI, m/z) 402 [M]þ; HRMS (ESI) calcd for
C25H21ClNO2 [M]þ 402.1255, found 402.1262.
9-Propylindole[2,3-c]-2,3-dihydropyridine[1,2-a]isoquinolizinium
Hexafluorostilbate (4m). In the same manner as described in the
preparation of 2a, 4m was obtained as yellow solid after puri-
fication by column chromatography with CH2Cl2/MeOH (20/1,
v/v) (yield 74%): 1H NMR (300 MHz, DMSO) δ 12.34 (s, 1H),
8.96 (d, J = 9.0 Hz, 1H), 8.20 (d, J = 7.5 Hz, 1H, 8.17 (s, 1H),
8.04 (t, J = 8.4 Hz, 1H), 7.89 (d, J = 8.1 Hz, 1H), 7.68 (d, J =
8.1 Hz, 2H), 7.47 (t, J = 6.9 Hz, 1H), 7.26 (t, J = 6.0 Hz, 1H),
3.42 (t, J = 5.4 Hz, 2H), 3.23 (t, J = 5.7 Hz, 2H), 1.85 (t, J = 7.5
Hz, 2H), 1.11 (t, J = 7.2 Hz, 3H), 0.90-0.80 (m, 2H); 13C NMR
(75 MHz, DMSO) δ 147.2 146.2 141.0 137.8 135.3 130.4 129.4
127.2 127.0 126.8 123.8 122.9 122.3 121.8 121.2 113.3 49.4 35.0
20.9 18.7 13.5; MS (ESI, m/z) 313 [M]þ; HRMS (ESI) calcd for
C22H21N2 [M]þ 313.1699, found 313.1685.
7.59-7.53 (m, 3H), 7.26 (t, J = 7.2 Hz, 1H), 4.57 (t, J = 4.2 Hz,
2H), 3.45 (t, J = 4.8 Hz, 2H); 13C NMR (75 MHz, DMSO) δ
161.8 146.1 145.0 141.2 137.6 135.7 132.2 132.1 131.1 130.6 130.1
129.5 128.1 127.8 127.2 123.8 123.3 122.8 121.3 121.2 116.3 116.0
113.4 52.4 18.5; MS (ESI, m/z) 365 [M]þ; HRMS (ESI) calcd for
C25H18FN2 [M]þ 365.1449, found 365.1449.
9-m-tolylindole[2,3-c]-2,3-dihydropyridine[1,2-a]isoquinolizin-
ium Hexafluorostilbate (4r). In the same manner as described in
the preparation of 2a, 4r was obtained as yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 74%): 1H NMR (300 MHz, DMSO) δ 12.48 (s,
1H), 9.06 (d, J = 8.4 Hz, 1H), 8.25 (d, J = 7.2 Hz, 2H), 8.22 (s,
1H), 8.13 (t, J = 8.4 Hz, 1H), 7.83 (d, J = 7.8 Hz, 2H), 7.71 (d,
J = 8.4 Hz, 2H), 7.57 (t, J = 6.6 Hz, 3H), 7.26 (t, J = 6.9 Hz,
1H), 4.60 (t, J = 6.3 Hz, 2H), 3.49 (t, J = 6.6 Hz, 2H), 2.46 (s,
3H); 13C NMR (75 MHz, DMSO) δ 146.1 141.2 138.5 137.7
133.7 131.0 130.5 130.4 129.9 129.6 128.9 127.8 127.2 126.8 126.6
123.8 123.6 123.3 122.8 121.3 121.2 113.4 52.5 21.0 18.6; MS
(ESI, m/z) 361 [M]þ; HRMS (ESI) calcd for C26H21N2 [M]þ
361.1699, found 361.1680.
2-Methyl-8-phenyl-5,6-dihydroisoquinolino[1,2-a]isoquinolizinium
Hexafluorostilbate (4s). In the same manner as described in the
preparation of 2a, 4s was obtained as yellow solid after purifica-
tion by column chromatography with CH2Cl2/MeOH (20/1, v/v)
(yield 72%): 1H NMR (300 MHz, CDCl3) δ 8.48-8.57 (dd, J =
12 Hz, J = 8.1 Hz, 1H), 8.08 (s, 1H), 7.90 (t, J = 7.5 Hz, 1H),
7.78-7.62 (m, 7H), 7.43 (s, 1H), 7.03 (d, J = 6.6 Hz, 2H), 4.59 (t,
J = 5.1 Hz, 2H), 3.18 (t, J = 5.7 Hz, 2H), 2.48 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 154.6 146.2 138.7 137.9 137.3 134.6 131.5
131.0 130.2 129.8 129.5 129.3 128.9 128.5 127.5 126.6 125.8 125.1
52.4 27.2 21.3; MS (ESI, m/z) 322 [M]þ; HRMS (ESI) calcd for
C24H20N [M]þ 322.1590, found 322.1599.
7-Phenylthieno[2,3-c]-2,3-dihydropyridine[1,2-a]isoquinolizinium
Hexafluorostilbate (4t). In the same manner as described in the
preparation of 2a, 4t was obtained as yellow solid after purifica-
tion by column chromatography with CH2Cl2/MeOH (20/1, v/v)
(yield 74%): 1H NMR (300 MHz, DMSO) δ 8.96 (d, J = 9.0 Hz,
1H), 8.18 (d, J = 8.1 Hz, 3H), 8.04 (t, J = 8.4 Hz, 1H), 7.89 (d,
J = 8.1 Hz, 2H), 7.68 (d, J = 8.1 Hz, 2H), 7.47 (t, J = 7.8 Hz,
2H), 7.26 (t, J = 7.8 Hz, 1H), 4.83 (t, J = 5.4 Hz, 2H), 3.23 (t,
J = 4.5 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 150.1 147.1 146.2
141.6 138.4 136.0 132.6 131.0 130.8 129.7 129.5 129.3 128.5 127.9
125.9 124.9 124.4 52.3 22.7; MS (ESI, m/z) 314 [M]þ; HRMS
(ESI) calcd for C21H16NS [M]þ 314.0998, found 314.1007.
2-Methoxy-8-phenyl-5,6-dihydroisoquinolino[1,2-a]isoquino-
lizinium Hexafluorostilbate (4u). Inthe same manner as described
in the preparation of 2a, 4u was obtained as yellow solid after
purification by column chromatography with CH2Cl2/MeOH
(20/1, v/v) (yield 70%): 1H NMR (300 MHz, CDCl3) δ 8.61 (d, J
= 9.3 Hz, 1H), 8.18 (d, J = 9.0 Hz, 1H), 8.09 (s, 2H), 7.79 (d, J =
6.6 Hz, 3H), 7.60-7,44 (m, 6H), 4.60 (s, 2H), 3.89 (s, 3H), 3.16 (s,
2H); 13C NMR (75 MHz, CDCl3) δ 158.5 154.4 146.4 138.8 135.8
132.2 130.8 130.7 130.6 130.3 130.1 129.3 129.2 128.4 127.5 126.1
125.3 119.4 118.8 56.0 52.8 26.9; MS (ESI, m/z) 338 [M]þ; HRMS
(ESI) calcd for C24H20NO [M]þ 338.1539, found 338.1540.
9-Chloropropylindole[2,3-c]-2,3-dihydropyridine[1,2-a]isoqui-
nolizinium Hexafluorostilbate (4n). In the same manner as de-
scribed in the preparation of 2a, 4n was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
1
MeOH (20/1, v/v) (yield 69%): H NMR (300 MHz, DMSO)
δ 12.36 (s, 1H), 8.96 (d, J = 8.1 Hz, 1H), 8.21 (d, J = 5.7 Hz,
1H), 8.18 (s, 1H), 7.89 (d, J = 7.8 Hz, 2H), 7.68 (d, J = 8.4 Hz,
2H), 7.48 (t, J = 6.9 Hz, 1H), 7.28 (d, J = 6.9 Hz, 1H), 4.83 (t,
J = 6.3 Hz, 2H), 3.87 (t, J = 6.6 Hz, 2H), 3.49 (t, J = 4.8 Hz,
2H), 2.30 (t, J = 6.9 Hz, 2H), 0.91-0.80 (m, 2H); 13C NMR (75
MHz, DMSO) δ 146.5 146.0 141.1 137.9 135.4 130.5 129.4
127.2 127.1 126.8 123.8 123.0 122.4 122.1 113.3 49.6 44.3 30.7
30.4 29.6; MS (ESI, m/z) 347 [M]þ; HRMS (ESI) calcd for
C22H20ClN2 [M]þ 347.1370, found 347.1326.
9-Phenylindole[2,3-c]-2,3-dihydropyridine[1,2-a]isoquinolizinium
Hexafluorostilbate (4o). In the same manner as described in the
preparation of 2a, 4o was obtained as yellow solid after pur-
ification by column chromatography with CH2Cl2/MeOH (20/
1, v/v) (yield 71%): 1H NMR (300 MHz, DMSO) δ 12.48 (s, 1H),
9.06 (d, J = 8.4 Hz, 1H), 8.33-8.13 (m, 3H), 7.84-7.69 (m, 6H),
7.50-7.27 (m, 2H), 7.25 (t, J = 8.1 Hz, 2H), 4.57 (d, J = 5.1 Hz,
2H), 2.11 (d, J = 5.4 Hz, 2H); 13C NMR (75 MHz, DMSO) δ
146.1 145.9 141.2 138.7 137.7 135.6 133.7 131.1 130.3 129.5 129.1
127.8 127.2 126.8 123.8 123.6 123.3 122.8 121.1 114.5 113.4 55.8
18.6; MS (ESI, m/z) 347 [M]þ; HRMS (ESI) calcd for C25H19N2
[M]þ 347.1543, found 347.1542.
9-Methoxyphenylindole[2,3-c]-2,3-dihydropyridine[1,2-a]iso-
quinolizinium Hexafluorostilbate (4p). In the same manner as
described in the preparation of 2a, 4p was obtained as yellow
solid after purification by column chromatography with
1
CH2Cl2/MeOH (20/1, v/v) (yield 72%): H NMR (300 MHz,
DMSO) δ 12.47 (s, 1H), 9.04 (d, J = 8.4 Hz, 1H), 8.26-8.14 (m,
3H), 8.11 (t, J = 6.9 Hz, 1H), 7.85-7.75 (m, 4H), 7.45 (t, J = 7.8
Hz, 1H), 7.25 (t, J = 7.5 Hz, 3H), 4.60 (t, J = 6.3 Hz, 2H), 3.90
(s, 3H), 2.89 (s, 1H), 2.73 (s, 1H); 13C NMR (75 MHz, DMSO) δ
160.0 146.0 141.1 137.7 135.3 134.6 134.5 131.2 130.5 130.3 128.5
127.7 127.1 126.8 125.8 123.8 123.2 122.7 121.3 121.1 117.2 114.4
113.3 55.5 52.3 28.8; MS (ESI, m/z) 377 [M]þ; HRMS (ESI)
calcd for C26H21N2O [M]þ 377.1648, found 377.1632.
Acknowledgment. We gratefully acknowledge financial sup-
port from the National Natural Science Foundation of China
(Grant Nos. 20721003 and 20872153), International Collabora-
tion Projects (Grant No. 20720102040), the 863 Hi-Tech Program
of China (Grant Nos. 2006AA020602 and 2006AA020402), and
National S&T Major Projects (Nos. 2009ZX09301-001,
2009ZX09501-001, and 2009ZX09501-010).
9-Fluorophenylindole[2,3-c]-2,3-dihydropyridine[1,2-a]isoquino-
lizinium Hexafluorostilbate (4q). In the same manner as de-
scribed in the preparation of 2a, 4q was obtained as yellow solid
after purification by column chromatography with CH2Cl2/
Supporting Information Available: Detailed experimental
MeOH (20/1, v/v) (yield 71%): H NMR (300 MHz, DMSO)
δ 12.50 (s, 1H), 9.06 (d, J = 8.1 Hz, 1H), 8.28 (s, 1H), 8.23 (t, J =
7.8 Hz, 2H), 7.82 (t, J = 8.4 Hz, 3H), 7.71 (d, J = 8.7 Hz, 2H),
procedures, characterization data, copies of H and 13C NMR
1
1
spectra for all products, and X-ray data for 2a (CIF). This material
is available free of charge via the Internet at http://pubs.acs.org.
5820 J. Org. Chem. Vol. 75, No. 17, 2010