New entry to bridged pentacyclic indolyltetrahydroisoquinoline skeleton via tandem s-alkylation and intramolecular C-Alkylation

Article abstract of DOI:10.1055/s-0029-1218534

An efficient, single-step synthesis of hitherto unknown indole-annulated pentacyclic indolylhydroisoquinolines via tandem S-alkylation and intramolecular C-alkylation of indolin-2-thiones with N-alkylisoquinolinium salts is reported. This new approach provides a powerful entry into polycyclic structures containing nitrogen and sulfur related to alkaloids. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-0029-1218534

LETTER
123
New Entry to Bridged Pentacyclic Indolyltetrahydroisoquinoline Skeleton via
Tandem S-Alkylation and Intramolecular C-Alkylation
New Entry to
i
d
r
Pentac
o
u
z
quinoline Skeleto
M
n
atloubi Moghaddam,* Salman Taheri, Zohreh Mirjafary, Hamdollah Saeidian
Laboratory of Organic Synthesis & Natural Products, Department of Chemistry, Sharif University of Technology, P. O. Box 11155-9516,
Tehran, Iran
E-mail: matloubi@sharif.edu
Received 18 August 2009
RO
RO
R
Abstract: An efficient, single-step synthesis of hitherto unknown
indole-annulated pentacyclic indolylhydroisoquinolines via tandem
S-alkylation and intramolecular C-alkylation of indolin-2-thiones
with N-alkylisoquinolinium salts is reported. This new approach
provides a powerful entry into polycyclic structures containing ni-
trogen and sulfur related to alkaloids.
RN
OR
I
OMe
Key words: thiooxindoles, pentacyclic heterocycles, tandem reac-
tion, indolyltetrahydroisoquinoline, isoquinolinium salts
MeN
HN
II
R3
NR1
The isoquinoline core is a structural motif common to a
large and diverse family of natural products that have
shown a remarkable array of biological activities.1 Among
the members of this family, those in which the nitrogen-
containing ring is partially hydrogenated, the 1,2,3,4-tet-
rahydroisoquinolines, constitute a major group in this
class of interesting alkaloids (compound I).2 Furthermore,
molecules that contain both indole and tetrahydroisoquin-
oline subunits possess interesting biological activities,
and find application in biogenetic type synthesis of miss-
ing alkaloids, systems related to naturally occurring alka-
loids, such as compound II and III (Figure 1).3
OMe
NR3
III
Figure 1
(Reissert reaction),6 trimethylsilylacetonitrile,7 allylsi-
lanes silyl enol ethers,8 diazoesters,9 and iodolactoniza-
tion.10 On the other hand, thioamides have been utilized as
synthons in the synthesis of heterocycles.11 As part of our
current research on the development of novel and efficient
protocols to heterocyclic systems using thioamides,12 we
now wish to report a hitherto unknown reaction that af-
fords bridged pentacyclic indolyltetrahydroisoquinoline
derivatives 3a–l via tandem reactions of N-alkylisoquino-
linium salts 1 with indolin-2-thiones 2 (Scheme 1). These
compounds may be considered as isoesteric analogues of
indolopavine derivatives since they are structurally relat-
ed to the natural pavine alkaloids.13
Much effort has been made to discover new reactions to
facilitate the construction of heterocycles containing in-
dole and tetrahydroisoquinoline nuclei. A current chal-
lenge in organic synthesis involves development of new
methodologies that afford complex molecules from rela-
tively simple starting materials via tandem reactions with
fewer synthetic steps and mild reaction conditions leading
to high yields.4
Initially we set out to investigate solvent and base effects
in the reaction of N-methylisoquinlinium salts and N-ethyl
indolin-2-thione as simple model substrates (Table 1).
The results showed that a base is required to achieve the
desired products and, in the optimized conditions, MeCN
Isoquinolinium salts represent important synthetic build-
ing blocks.5 They are readily generated by alkylation or
acylation of isoquinolines and have been used in a number
of reactions, for example, with Grignard reagents, cyanide
R2
N
K2CO3, MeCN
NR1
+
S
N+
X–
r.t., 3 h
R1
N
S
R2
1
2
3a–l
X = I, Br
Scheme 1
SYNLETT 2010, No. 1, pp 0123–0127
x
x.
x
x.
2
0
1
0
Advanced online publication: 02.12.2009
DOI: 10.1055/s-0029-1218534; Art ID: D22509ST
© Georg Thieme Verlag Stuttgart · New York

124
F. M. Moghaddam et al.
LETTER
and K2CO3 were found to be the best solvent and base (J = 16.0 Hz) at d = 3.24 ppm, and Hd as a double doublet
(Table 1, entry 5).
(J = 16.0, 5.0 Hz) at d = 3.66 ppm (Figure 2). This can be
related to previously reported spectra which were inter-
preted as representing a system in which the bridgehead
hydrogens are coupled appreciably with only one of the
two adjacent hydrogens (i.e., Hb coupled with Hd but not
Table 1 Optimization of Reaction Conditionsa
Entry Base
Solvent
CH2Cl2
CH2Cl2
toluene
acetone
MeCN
MeCN
MeCN
MeCN
H2O
Temp (°C) Time (h) Yield (%)b
1
with Hc).14 The H-decoupled 13C NMR spectrum of 3g
1
2
3
4
5
6
7
8
9
no base
r.t.
r.t.
r.t.
r.t.
r.t.
80
r.t.
r.t.
r.t.
4
4
4
4
2
4
4
4
4
n.r.
55
5
showed 22 distinct resonances in agreement with the pro-
posed structure. The 13C DEPT experiment showed the
presence of a resonance at d = 36.5 ppm readily recog-
nized as the methylene carbon (C-12), a resonance at d =
52.6 ppm as the bridgehead carbon (C-13), a resonance at
d = 42.1 ppm as the N-methyl carbon, a resonance at d =
71.3 ppm as the N–CH–S carbon, 12 distinct resonances
for the aromatic methine carbons, and 6 other quaternary
carbons. Further evidence for the bridged structure is giv-
en by the HMBC spectrum in which the key correlations
between the methyl proton at d = 2.69 (NMe) ppm and
carbons at d = 52.6 (C-13) and 71.3 (C-7) ppm indicate
that the connection points of the indole ring and the tet-
rahydroisoquinoline ring are at C-13 and C-7. Some key
HMBC correlations are shown in Figure 2.
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
Et3N
40
86
80
85
30
30
K2CO3
a Reaction conditions: solvent(5 mL), N-methyl isoquinolinum salt
(1 mmol), K2CO3 (1 mmol), and N-ethylindolin-2-thione (1 mmol).
b Isolated products.
In view of the success of the above reaction, we explored
the scope of this promising reaction by varying the struc-
ture of the N-alkylisoquinolinium salt 1 and indolin-2-
thione 2 components (Table 2). The reaction proceeds
very cleanly under mild conditions at room temperature
and no side reactions were observed under these condi-
tions.
The 1H NMR, 13C NMR, 2DNMR (H-H COSY, HMQC,
HMBC) spectra and elemental analysis of the products
clearly indicated the formation of 3a–l. For example, in
the 1H NMR spectrum of 3g the bridgehead Ha hydrogen
appears as a singlet at d = 5.69 ppm, the bridgehead Hb as
a doublet (J = 5.0 Hz) at d = 4.58 ppm, Hc as a doublet
Table 2 Synthesis of Pentacyclic Indolyltetrahydroisoquinoline Derivatives
R2
N
K2CO3, MeCN
+
S
N
R1
S
N+
X–
r.t., 3 h
R1
N
R2
2
3a–j
1
Entry
R1
R2
Product
Yield (%)a
1
Me
Et
H
H
H
H
3a
3b
3c
3d
3e
3f
86
82
75
64
81
95
89
68
90
91
86
88
2
Et
3
Bn
4
propargyl
5
Me
6
Me
Me
Ph
Ph
Ph
Me
Et
7
Me
3g
3h
3i
8
propargyl
Et
9
10
11
12
Et
3j
Et
3k
3l
All
Me
a Isolated yield.
Synlett 2010, No. 1, 123–127 © Thieme Stuttgart · New York

LETTER
New Entry to Bridged Pentacyclic Indolyltetrahydroisoquinoline Skeleton
125
1
2
Hb
Hd Hc
General Procedure for the Synthesis of Polycyclic Indole Deriv-
atives 3a–l
11
8
13
13a
13b
3
11a
12
10
9
N
4
14
4a
Me
A mixture of an isoquinolinium salt 1 (1 mmol), indoline-2-thione
2 (1 mmol), and K2CO3 (0.14 g, 1 mmol) in MeCN (5 mL) was
stirred at r.t. for 3 h. The progress of the reaction was monitored by
TLC. After completion of the reaction, the solvent was removed un-
der reduced pressure, and the residue was separated by flash chro-
5a
7a
N
5
Ph
S
7
6
Ha
Figure 2 The key HMBC correlations of compound 3g
In the next stage, we investigated the scope of the reaction matography on a silica gel column with PE–EtOAc (10:1) as eluent
to obtain pure products. The structures of the products were con-
with a linear thioamide, 4-(2-phenylethanethioyl)morpho-
firmed by the 1H NMR, 13C NMR, 2D NMR (H-H COSY, HMQC,
line, as a tertiary thioamide and thioacetamide and
thiobenzamide as primary thioamides under the optimized
HMBC) spectroscopic and elemental analysis.16
reaction conditions but no reaction was observed, and the
initial isoquinolinium salt and thioamide were recovered.
Acknowledgment
A plausible mechanism for the formation of product is
shown in Scheme 2. Indolin-2-thione 1 undergoes S-alky-
lation with the N-alkylisoquinolinium salt 2 affording the
intermediate 4. Subsequent intramolecular nucleophilic
cyclization of 4 gives the desired product. All attempts to
isolate intermediate 4 failed; although nucleophilic addi-
tion of indolic systems to olefins to form a carbon–carbon
bond have been widely reported in the literature,15 but ef-
fective alkylation of an indole with an olefin requires
strong Lewis acids, an electron-deficient Michael accep-
tor, or prolonged heating under highly acidic conditions.
Interestingly, the present intramolecular alkylation of in-
dole takes place under mild conditions without any cata-
lysts.
We would like to acknowledge the Islamic Development Bank
(IDB) for financial backing to purchase a 500 MHz NMR spectro-
meter.
References and Notes
(1) Shamma, M. Isoquinoline Alkaloids, Chemistry and
Pharmacology; Academic Press: New York, 1972.
(2) (a) Scott, J. D.; Williams, R. M. Chem. Rev. 2002, 102,
1669. (b) Arai, T.; Kubo, A. The Alkaloids, Vol. 21;
Academic: New York, NY, 1983, 55–100. (c) Varadinova,
T. L.; Shishkov, S. A.; Ivanovska, N. D.; Velcheva, M. P.;
Danghaaghin, S.; Samadanghiin, Z.; Yansanghiin, Z.
Phytother. Res. 1996, 10, 414. (d) Fujiwara, N.; Ueda, Y.;
Ohashi, N. Bioorg. Med. Chem. Lett. 1996, 6, 743.
(3) (a) Morrison, G. C.; Waite, R. O.; Serafin, F.; Shavel, J.
J. Org. Chem. 1967, 32, 2551. (b) Zinnes, H.; Zuleski, F. R.;
Shavel, J. J. Org. Chem. 1968, 33, 3605.
(4) (a) Yadav, J. S.; Reddy, B. V. S.; Yadav, N. N.; Gupta, M.
K. Tetrahedron Lett. 2008, 49, 2815. (b) Parenty, A. D. C.;
Smith, L. V.; Pickering, A. L.; Long, D. L.; Cronin, L.
J. Org. Chem. 2004, 69, 5934. (c) Ho, T. L. Tandem
Organic Reactions; Wiley and Sons: New York, 1992.
(d) Overman, L. E.; Velthuisen, E. J. J. Org. Chem. 2006, 71,
1581. (e) Tietze, L. F. Chem. Rev. 1996, 96, 115. (f) Wang,
K. K. Chem. Rev. 1996, 96, 207.
(5) Scriven, E. F. V. Pyridines and their Benzo Derivatives:(ii)
Reactivity at Ring Atoms, In Comprehensive Heterocyclic
Chemistry, Part 2A, Vol. 2; Boulton, A. J.; McKillop, A.;
Katritzky, A. R.; Rees, C. W., Eds.; Elsevier Science:
Oxford, 1984, Chap. 2.05.
(6) Bradley, W.; Jeffrey, S. J. Chem. Soc. 1954, 2770.
(7) (a) Diaba, F.; Le Houerou, C.; Grignon-Dubios, M.; Gerval,
P. J. Org. Chem. 2000, 65, 907. (b) Yamaguchi, R.; Hatano,
B.; Nakaysau, T.; Kozima, S. Tetrahedron Lett. 1997, 38,
403.
R1N+
2
K2CO3
S–
S
N
N
R2
R2
1
H+
+NR1
S
NR1
S
H+
N
R2
N
R2
4
NR1
NR1
H
– H+
N+
R2
N
R2
S
S
3a–l
(8) (a) Akiba, K.; Nishihara, Y.; Wada, M. Tetrahedron Lett.
1983, 24, 5269. (b) Diaba, F.; Le Houerou, C.; Grignon-
Dubois, M.; Rezzonico, B.; Gerval, P. Eur. J. Org. Chem.
2000, 2915. (c) Itoh, T.; Nagata, K.; Miyazaki, M.;
Kameoka, K.; Ohsawa, A. Tetrahedron 2001, 57, 8827.
(d) Katritzky, A. R.; Zhang, S.; Kurz, T.; Wang, M. Org.
Lett. 2001, 3, 2807. (e) Comins, D. L.; Sandelier, M. J.;
Grillo, T. A. J. Org. Chem. 2001, 66, 6829.
(9) Yadav, J. S.; Reddy, B. V. S.; Gupta, M. K.; Prabhakar, A.;
Jagadeesh, B. Chem. Commun. 2004, 2124.
(10) Ullah, E.; Rotzoll, S.; Schmidt, A.; Michalik, D.; Langer, P.
Tetrahedron Lett. 2005, 46, 8997.
Scheme 2
In conclusion, we have reported a novel and highly effi-
cient method for the synthesis of bridged polycyclic in-
dolyltetrahydroisoquinolines. This method offers several
advantages, such as high conversions, high selectivity,
and experimental simplicity starting from easily accessi-
ble starting materials that make it a useful and attractive
strategy for the preparation of polycyclic indolyltetrahy-
droisoquinolines in a single-step operation.
(11) Jagodzinski, T. S. Chem. Rev. 2003, 103, 197.
Synlett 2010, No. 1, 123–127 © Thieme Stuttgart · New York

126
F. M. Moghaddam et al.
LETTER
(12) (a) Moghaddam, F. M.; Saeidian, H.; Mirjafary, Z.; Taheri,
S.; Kheirjou, S. Synlett 2009, 1047. (b) Moghaddam, F. M.;
Mirjafary, Z.; Saeidian, H.; Javan, M. J. Synlett 2008, 892.
(c) Saeidian, H.; Sadeghi, A.; Mirjafary, Z.; Moghaddam,
F. M. Synth. Commun. 2008, 38, 2043. (d) Moghaddam,
F. M.; Saeidian, H.; Mirjafary, Z.; Sadeghi, A. Lett. Org.
Chem. 2007, 4, 576. (e) Moghaddam, F. M.; Saeidian, H.;
Mirjafary, Z.; Taheri, S. J. Sulfur Chem. 2006, 27, 545.
(f) Moghaddam, F. M.; Zali Boinee, H. Synlett 2005, 1612.
(g) Moghaddam, F. M.; Zali Boinee, H. Tetrahedron 2004,
60, 6085. (h) Moghaddam, F. M.; Zali Boinee, H.
Tetrahedron Lett. 2003, 44, 6253.
7.60. Found: C, 78.66; H, 5.83; N, 7.63.
14-Prop-2-yn-1-yl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3d)
White solid; mp 131–133 °C. 1H NMR (500 MHz, CDCl3):
d = 7.65 (s, 1 H, NH), 7.49 (d, J = 7.5 Hz, 1 H), 7.38 (d,
J = 7.5 Hz, 1 H), 7.12–7.26 (m, 5 H), 7.03 (d, J = 7.5 Hz, 1
H), 6.01 (s, 1 H), 4.68 (d, J = 5.5 Hz, 1 H), 3.62 (dd, J = 16.0,
2.5 Hz, 1 H), 3.61 (dd, J = 15.5, 5.5 Hz, 1 H), 3.51 (dd,
J = 16.0, 2.5 Hz, 1 H), 3.13 (d, J = 15.5 Hz, 1 H), 3.39 (t,
J = 2.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 136.8
(C), 135.5 (C), 132.9 (C), 129.5 (CH), 128.0 (CH), 127.7
(CH), 127.1 (C), 126.3 (CH), 125.8 (C), 121.4 (CH), 120.1
(CH), 116.7 (CH), 110.6 (CH), 102.7 (C), 79.8 (C), 73.7 (C),
68.3 (CH), 51.0 (CH), 43.2 (CH2), 36.5 (CH2). Anal. Calcd
for C20H16N2S: C, 75.92; H, 5.10; N, 8.85. Found: C, 75.62;
H, 5.23; N, 8.83.
(13) Gözler, B. The Alkaloids: Chemistry and Pharmacology
1987, 31, 317.
(14) (a) Anet, F. A. L. Can. J. Chem. 1961, 89, 789. (b) Martell,
M. J.; Soine, T. O.; Kier, L. B. J. Am. Chem. Soc. 1963, 85,
1022.
(15) (a) Youn, S. W.; Pastine, S. J.; Sames, D. Org. Lett. 2004, 6,
581. (b) Liu, C.; Han, X.; Wang, X.; Widenhoefer, R. A.
J. Am. Chem. Soc. 2004, 126, 3700. (c) Morrison, G. C.;
Waite, R. O.; Serafin, F.; Shavel, J. J. Org. Chem. 1967, 32,
2551. (d) Zhang, Z.; Wang, X.; Widenhoefer, R. A. Chem.
Commun. 2006, 3717.
14-Methyl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3e)
Yellow solid; mp 125–127 °C. 1H NMR (500 MHz, CDCl3):
d = 7.67 (br s, NH, 1 H), 7.49 (d, J = 7.5 Hz, 1 H), 7.36 (d,
J = 8.0 Hz, 1 H), 7.11–7.22 (m, 5 H), 7.04 (d, J = 7.5 Hz, 1
H), 5.73 (s, 1 H), 4.49 (d, J = 5.0 Hz, 1 H), 3.59 (dd, J = 16.0,
5.0 Hz, 1 H), 3.13 (d, J = 16.0 Hz, 1 H), 2.67 (s, 3 H). 13
C
(16) Spectroscopic Data
NMR (125 MHz, CDCl3): d = 137.36 (C), 135.42 (C), 132.8
(C), 129.6 (CH), 127.9 (CH), 127.5 (CH), 127.4 (C), 126.2
(CH), 126.1 (C), 121.2 (CH), 119.9 (CH), 116.6 (CH), 110.6
(CH), 102.7 (C), 72.0 (CH), 52.3 (CH), 42.0 (CH3), 36.5
(CH2). Anal. Calcd for C18H16N2S: C, 73.94; H, 5.52 N, 9.58.
Found: C, 74.12; H, 5.71; N, 9.55.
5-Ethyl-14-methyl-5,7,12,13-tetrahydro-7,13-
epimino[2]benzothiocino[3,4-b]indole (3a)
Pale yellow solid; mp 163–165 °C. 1H NMR (500 MHz,
CDCl3): d = 7.54 (d, J = 7.5 Hz, 1 H), 7.37 (d, J = 8.0 Hz, 1
H), 7.13–7.32 (m, 5 H), 7.05 (d, J = 7.5 Hz, 1 H), 5.78 (s, 1
H), 4.53 (d, J = 5.5 Hz, 1 H), 4.06 (m, 2 H), 3.61 (dd,
J = 15.5, 5.5 Hz, 1 H), 3.15 (d, J = 15.5 Hz, 1 H), 2.65 (s, 3
H), 1.31 (t, J = 7.1 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 137.4 (C), 136.1 (C), 132.9 (C), 129.6 (CH), 128.0 (C),
127.9 (C), 127.8 (CH), 127.6 (CH) 126.1 (CH), 120.4 (CH),
119.3 (CH), 116.6 (CH), 108.7 (CH), 101.8 (C), 71.7 (CH),
52.6 (CH), 42.0 (CH3), 38.4 (CH2), 36.6 (CH2), 15.4 (CH3).
Anal. Calcd for C20H20N2S: C, 74.96; H, 6.29; N, 8.74.
Found: C, 75.01; H, 6.31; N, 8.77.
5,14-Dimethyl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3f)
Yellow solid; mp 164–166 °C. 1H NMR (500 MHz, CDCl3):
d = 7.51 (m, 1 H), 7.37 (d, J = 7.5 Hz, 1 H), 7.13–7.28 (m, 5
H), 7.04 (d, J = 7.5 Hz, 1 H), 5.78 (s, 1 H), 4.52 (d, J = 5.0
Hz, 1 H), 3.60 (dd, J = 15.5, 5.5 Hz, 1 H), 3.56 (s, 3 H), 3.15
(d, J = 15.5 Hz, 1 H), 2.63 (s, 3 H). 13C NMR (125 MHz,
CDCl3): d = 137.4 (C), 137.1 (C), 132.9 (C), 129.5 (CH),
128.9 (C), 127.9 (CH), 127.6 (CH), 126.1 (CH), 119.3 (CH),
116.5 (CH), 108.5 (CH), 101.7 (C), 71.9 (CH), 52.6 (CH),
41.9 (CH3), 36.6 (CH2), 29.7 (CH3). Anal. Calcd for
C19H18N2S: C, 74.47; H, 5.92; N, 9.14. Found: C, 74.32; H,
6.11; N, 9.18.
14-Ethyl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3b)
White solid; mp 107–109 °C. 1H NMR (500 MHz, CDCl3):
d = 7.60 (br s, NH, 1 H), 7.47 (d, J = 7.5 Hz, 1 H), 7.36 (d,
J = 8.0 Hz, 1 H), 7.25 (d, J = 7.5 Hz, 1 H), 7.19 (t, J = 8.0
Hz, 1 H), 7.10–7.16 (m, 3 H), 7.03 (d, J = 8.0 Hz, 1 H), 5.86
(s, 1 H), 4.60 (d, J = 5.0 Hz, 1 H), 3.55 (dd, J = 16.0, 5.0 Hz,
1 H), 3.12 (d, J = 16.0 Hz, 1 H), 2.88 (m, 1 H), 2.73 (m, 1 H),
1.30 (t, J = 7.0 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 137.4 (C), 5.3 (C), 135.2 (C), 129.6 (CH), 127.9 (CH),
127.6 (CH), 127.4 (C), 126.7 (C), 126.2 (CH), 121.1 (CH),
119.9 (CH), 116.6 (CH), 116.5 (C), 110.5 (CH), 103.1 (C),
70.2 (CH), 50.6 (CH), 47.8 (CH2), 36.5 (CH2), 13.1 (CH3).
Anal. Calcd for C19H18N2S: C, 74.47; H, 5.92; N, 9.14.
Found: C, 74.92; H, 6.11; N, 9.25.
14-Methyl-5-phenyl-5,7,12,13-tetrahydro-7,13-
epimino[2]benzothiocino[3,4-b]indole (3g)
Yellow solid; mp 170–172 °C. 1H NMR (500 MHz, CDCl3):
d = 7.59 (d, J = 8.0 Hz, 1 H), 7.53 (t, J = 7.5 Hz, 1 H), 7.52
(d, J = 7.5 Hz, 1 H), 7.43 (m, 3 H), 7.30 (t, J = 8.5 Hz, 2 H),
7.23 (t, J = 7.5 Hz, 1 H), 7.08–7.18 (m, 4 H), 5.69 (s, 1 H),
4.58 (d, J = 5.0 Hz, 1 H), 3.66 (dd, J = 16.0, 5.0 Hz, 1 H),
3.24 (d, J = 16.0 Hz, 1 H), 2.69 (s, 3 H). 13C NMR (125
MHz, CDCl3): d = 137.45 (C), 137.4 (C), 137.2 (C), 132.7
(C), 129.7 (CH), 129.6 (CH), 129.0 (CH), 128.2 (CH), 128.0
(CH), 127.8 (CH), 127.7 (CH), 127.4 (CH), 126.2 (CH),
121.3 (CH), 120.4 (CH), 116.6 (CH), 109.9 (CH), 103.5 (C),
71.4 (CH), 52.6 (CH), 42.1 (CH3), 36.5 (CH2). Anal. Calcd
for C22H20N2S: C, 78.23; H, 5.47; N, 7.60. Found: C, 78.37;
H, 5.80; N, 7.64.
14-Benzyl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3c)
Yellow solid; mp 88–90 °C. 1H NMR (500 MHz, CDCl3):
d = 7.68 (br s, NH, 1 H), 7.48 (d, J = 7.0 Hz, 2 H), 7.44 (d,
J = 7.5 Hz, 1 H), 7.38 (t, J = 8.0 Hz, 2 H), 7.12–7.36 (m, 7
H), 7.04 (d, J = 7.5 Hz, 1 H), 5.72 (s, 1 H), 4.58 (d, J = 5.5
Hz, 1 H), 4.02 (d, J = 13.5 Hz, 1 H), 3.85 (d, J = 13.5 Hz, 1
H), 3.59 (dd, J = 16.0, 5.5 Hz, 1 H), 3.10 (d, J = 16.0 Hz, 1
H). 13C NMR (125 MHz, CDCl3): d = 138.0 (C), 137.4 (C),
135.4 (C), 133.3 (C), 129.6 (CH), 129.5 (CH), 128.9 (CH),
127.9 (CH), 127.8 (CH), 127.6 (CH), 127.3 (C), 126.6 (C),
126.1 (CH), 121.2 (CH), 119.9 (CH), 116.7 (CH), 110.5
(CH), 103.1 (C), 70.2 (CH), 58.1 (CH2), 50.8 (CH), 36.5
(CH2). Anal. Calcd for C24H20N2S: C, 78.23; H, 5.47. N,
14-Prop-2-yn-1-yl-5,7,12,13-tetrahydro-7,13-
epimino[2]benzothiocino[3,4-b]indole (3h)
Yellow solid; mp 183–185 °C; 1H NMR (500 MHz, CDCl3):
d = 7.79 (d, J = 8.0 Hz, 1 H), 7.49–7.56 (m, 4 H), 7.04–7.46
(m, 4 H), 7.10–7.26 (m, 5 H), 5.63 (s, 1 H), 5.41 (d, J = 6.0
Hz, 1 H), 3.86 (dd, J = 16.0, 6.0 Hz, 1 H), 3.31–3.40 (m, 3
H), 2.38 (t, J = 2.5 Hz, 1 H). 13C NMR (125 MHz, CDCl3):
d = 138.4 (C), 137.3 (C), 137.1 (C), 133.4 (C), 129.8 (CH),
129.6 (CH), 129.4 (C), 128.1 (C), 127.9 (CH), 127.6 (CH),
127.3 (CH), 125.2 (CH), 121.2 (CH), 120.3 (CH), 116.6
Synlett 2010, No. 1, 123–127 © Thieme Stuttgart · New York

LETTER
New Entry to Bridged Pentacyclic Indolyltetrahydroisoquinoline Skeleton
127
(CH), 109.8 (CH), 103.9 (C), 80.3 (C) 74.6 (C) 69.3 (CH),
50.9 (CH), 47.8 (CH2), 36.6 (CH2).
14-Ethyl-5-phenyl-5,7,12,13-tetrahydro-7,13-
5,14-Diethyl-5,7,12,13-tetrahydro-7,13-epimino[2]-
benzothiocino[3,4-b]indole (3k)
Pale yellow solid; mp 151–153 °C. 1H NMR (500 MHz,
CDCl3): d = 7.54 (d, J = 7.5 Hz, 1 H), 7.39 (d, J = 7.5 Hz, 1
H), 7.31 (d, J = 7.5 Hz, 1H), 7.13–7.22 (m, 4 H), 7.05 (d,
J = 7.5 Hz, 1 H), 4.65 (d, J = 5.0 Hz, 1 H), 4.02 (m, 2 H),
3.58 (dd, J = 15.5, 5.0 Hz, 1 H), 3.16 (d, J = 15.5 Hz, 1 H),
2.89 (m, 1 H), 2.73 (m, 1 H), 1.33 (t, J = 7.0 Hz, 3 H), 1.31
(t, J = 7.0 Hz, 3 H). 13C NMR (125 MHz, CDCl3): d = 137.5
(C), 136.0 (C), 133.4 (C), 129.6 (CH), 128.6 (C), 127.89 (C),
127.83 (CH), 127.74 (CH) 126.1 (CH), 120.4 (CH), 119.27
(CH), 116.59 (CH), 108.6 (CH), 102.2 (C), 69.8 (CH), 50.8
(CH), 47.8 (CH2), 38.4 (CH2), 36.7 (CH2), 15.4 (CH3), 13.1
(CH3). Anal. Calcd for C21H22N2S: C, 75.41; H, 6.63; N,
8.38. Found: C, 75.84; H, 6.57; N, 8.29.
epimino[2]benzothiocino[3,4-b]indole (3i)
Pale yellow solid; mp 178–180 °C. 1H NMR (500 MHz,
CDCl3): d = 7.57 (d, J = 7.5 Hz, 1 H), 7.51 (t, J = 7.5 Hz, 2
H), 7.30–7.43 (m, 5 H), 7.20 (t, J = 7.5 Hz, 1 H), 7.07–7.18
(m, 4 H), 5.82 (s, 1 H), 4.68 (d, J = 5.0 Hz, 1 H), 3.62 (dd,
J = 15.5, 5.5 Hz, 1 H), 3.22 (d, J = 15.5 Hz, 1 H), 2.92 (m, 1
H), 2.78 (m, 1 H), 1.32 (t, J = 7.2 Hz, 3 H). 13C NMR (125
MHz, CDCl3): d = 137.4 (C), 137.2 (C), 137.1 (C), 133.1
(C), 129.7 (CH), 129.6 (CH), 129.5 (C), 128.1 (C), 127.9
(CH), 127.8 (CH), 127.3 (CH), 126.2 (CH), 121.2 (CH),
120.3 (CH), 116.6 (CH), 109.8 (CH), 103.9 (C), 69.3 (CH),
50.9 (CH), 47.8 (CH2), 36.6 (CH2), 13.2 (CH3).
14-Ethyl-5-methyl-5,7,12,13-tetrahydro-7,13-
epimino[2]benzothiocino[3,4-b] indole (3j)
14-Allyl-5-methyl-5,7,12,13-tetrahydro-7,13-epimino-
[2]benzothiocino[3,4-b]indole (3l)
Pale yellow solid; mp 167–169 °C. 1H NMR (500 MHz,
CDCl3): d = 7.50 (d, J = 7.5 Hz, 1 H), 7.38 (d, J = 8.0 Hz, 1
H), 7.12–7.27 (m, 5 H), 7.03 (d, J = 7.5 Hz, 1 H), 4.63 (d,
J = 4.5 Hz, 1 H), 3.56 (dd, J = 16.0, 4.5 Hz, 1 H), 3.50 (s, 3
H), 3.13 (d, J = 16.0 Hz, 1 H), 2.86 (m, 1 H), 2.71 (m, 1 H),
1.30 (t, J = 7.0 Hz, 3 H). 13C NMR (125 MHz, CDCl3):
d = 137.4 (C), 137.0 (C), 133.4 (C), 129.5 (CH), 129.4 (CH),
127.8 (CH), 127.7 (CH), 127.6 (C) 126.1 (CH), 120.4 (CH),
119.3 (CH), 116.4 (CH), 108.5 (CH), 102.1 (C), 70.0 (CH),
50.8 (CH), 47.81 (CH2), 36.7 (CH2), 29.7 (CH3), 13.1 (CH3).
Anal. Calcd for C20H20N2S; C, 74.92; H, 6.29; N, 8.74.
Found: C, 75.10; H, 6.48; N, 8.88.
White solid; mp 167–169 °C. 1H NMR (500 MHz, CDCl3):
d = 7.51 (d, J = 7.5 Hz, 1 H), 7.38 (d, J = 7.5 Hz, 1 H), 7.29
(d, J = 7.5 Hz, 1 H), 7.13–7.23 (m, 4 H), 7.05 (d, J = 7.5 Hz,
1 H), 6.05 (m, 1 H), 5.87 (s, 1 H), 5.41 (d, J = 17.0 Hz, 1 H),
5.32 (d, J = 10.0 Hz, 1 H), 4.64 (d, J = 4.5 Hz, 1 H), 3.61 (dd,
J = 15.5, 4.5 Hz, 1 H), 3.57 (s, 3 H), 3.48 (dd, J = 14.0, 6.0
Hz, 1 H), 3.30 (dd, J = 14.0, 6.0 Hz, 1 H), 3.15 (d, J = 16.0
Hz, 1 H). 13C NMR (125 MHz, CDCl3): d = 137.4 (C), 137.1
(C), 134.9 (CH), 133.4 (C), 129.6 (CH), 129.2 (C), 127.9
(CH), 127.7 (CH), 127.5 (C) 126.1 (CH), 120.5 (CH), 119.4
(CH), 119.3 (C), 116.6 (CH), 108.6 (C), 102.16 (CH2), 69.8
(CH), 56.8 (CH2), 50.9 (CH), 36.7 (CH2), 29.8 (CH3). Anal.
Calcd for C21H20N2S: C, 75.87; H, 6.06; N, 8.43. Found: C,
75.92; H, 6.14; N, 8.52.
Synlett 2010, No. 1, 123–127 © Thieme Stuttgart · New York

Copyright of Synlett is the property of Georg Thieme Verlag Stuttgart and its content may not
be copied or emailed to multiple sites or posted to a listserv without the copyright holder's
express written permission. However, users may print, download, or email articles for
individual use.