Synthesis of novel rigid analogs of tryptamine as potential serotonin ligands through Pd(0)-catalyzed diaryl coupling reactions

Article abstract of DOI:10.1080/00397910802139205

A series of novel tetracyclic 6-thia-5a-aza-acephenanthrylene derivatives 7 were synthesized by rigidization of the arylsulfonyl/carbonyl/methyl moiety through C7 of indole, which was achieved under Heck conditions. The strategy of altering the palladium-

Full text of DOI:10.1080/00397910802139205

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Synthesis of Novel Rigid
Analogs of Tryptamine as
Potential Serotonin Ligands
through Pd(0)-Catalyzed Diaryl
Coupling Reactions
Ramasastri Kambhampati a , Prabhakar Kothmirkar
a , Amol D. Deshpande a , Sobhanadri Arepalli a ,
Kameswara Rao Karturi a , Narasimha Reddy G.
Pamuleti a , Anil K. Shinde a & Ramakrishna V. S.
Nirogi a
a Medicinal Chemistry Discovery Research, Suven
Life Sciences Ltd, Hyderabad, India
Version of record first published: 11 Jul 2008
To cite this article: Ramasastri Kambhampati, Prabhakar Kothmirkar, Amol D.
Deshpande, Sobhanadri Arepalli, Kameswara Rao Karturi, Narasimha Reddy G.
Pamuleti, Anil K. Shinde & Ramakrishna V. S. Nirogi (2008): Synthesis of Novel Rigid
Analogs of Tryptamine as Potential Serotonin Ligands through Pd(0)-Catalyzed Diaryl
Coupling Reactions, Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:14, 2419-2428
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Synthetic Communications1, 38: 2419–2428, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910802139205
Synthesis of Novel Rigid Analogs of Tryptamine
as Potential Serotonin Ligands through Pd(0)-
Catalyzed Diaryl Coupling Reactions
Ramasastri Kambhampati, Prabhakar Kothmirkar,
Amol D. Deshpande, Sobhanadri Arepalli, Kameswara Rao Karturi,
Narasimha Reddy G. Pamuleti, Anil K. Shinde, and
Ramakrishna V. S. Nirogi
Medicinal Chemistry, Discovery Research, Suven Life Sciences Ltd,
Hyderabad, India
Abstract: A series of novel tetracyclic 6-thia-5a-aza-acephenanthrylene derivatives
7 were synthesized by rigidization of the arylsulfonyl=carbonyl=methyl moiety
through C7 of indole, which was achieved under Heck conditions. The strategy of
altering the palladium–bromine exchange site produced target products.
Keywords: Heck reaction; Tetracyclic 6-thia-5a-aza-acephenanthrylene; Tryptamine
INTRODUCTION
Diaryl coupling using the Heck reaction is one of the best-known meth-
odologies in organic chemistry.[1–4] There are several reports on use of
intramolecular Heck reaction for the preparation of polycyclic ring sys-
tems.[5] In our efforts to synthesize the compound 7 for the ongoing sero-
tonin receptor ligands[6] program, we largely used route 1 of Scheme 1.
However, to get the potent serotonin ligands, we were more inter-
ested in a compound with appropriate substituents in the D-ring and
unsubstituted C2 of indole. We realized that the site for palladium
bromine exchange, which was the ortho bromo on the aryl sulfonyl=
carbonyl=methyl ring, could be changed to C7 of indole. This strategy
Received April 12, 2007
Address correspondence to Ramakrishna V. S. Nirogi, Medicinal Chemistry,
Discovery Research, Suven Life Science, Serene Chambers, Road No. 7, Banjara
Hills, Hyderabad 500 034, India. E-mail: ramakrishna_nirogi@yahoo.co.in
2419

2420
R. Kambhampati et al.
Scheme 1. Synthesis of rigid analogs of tryptamine.
would not only eliminate the need for multiply substituted aryl sulfonyl
chlorides but also give the required product unambiguously. When N-
(substituted) arylsulfonyl-7-bromotryptamines were subjected to the Heck
cyclization under similar conditions, derivatives 7 were obtained in better
yields and purities. Possible steric instability of the intermediate palladium
complex could be one of the reasons for the better reaction rates.
RESULTS AND CONCLUSIONS
The general synthetic strategy used for the synthesis of title compounds 7
has been summarized in Scheme 1. Various substituted tryptamines 4
were either obtained commercially or synthesized using various literature
Scheme 2. Synthesis of substituted tryptamines.

Rigid Analogs of Tryptamine
2421
methods.[7] Treatment of substituted tryptamines 4 with the base and the
desired substituted aryl sulfonyl=carbonyl=methyl chlorides in tetra-
hydrofuran (THF) at rt yielded the intermediates 5 and 6, which were
isolated and fully characterized. The IR spectrum of these products
generally showed absorption bands at 1350 and 1175 cmꢀ1 for ꢀSO2
and at 1670 cmꢀ1 for ꢀCO. They were cyclized using the various pal-
ladium catalysts to get the desired compounds 7, which were confirmed
with spectral data.
Synthesis of tryptamines was achieved by the route depicted in
Scheme 2. The appropriately substituted indoles were converted to their
3-formyl analogs 1. Its IR spectrum showed the presence of a ꢀCHO
peak at 1710 cmꢀ1. 3-Formyl indoles were then condensed with nitro-
methane under alkaline conditions. The product 2 was reduced using
lithium aluminium hydride to the corresponding tryptamines, 3, which
were further dimethylated using formaldehyde and sodium cyanoboro-
hydride to the substituted tryptamines 4.
Most of the compounds showed relatively better yields and purities
when synthesized by route 2, and the reaction times were also relatively
lower, mainly because of the better impurity profile of the compounds
obtained. Some of the compounds for which the respective sulfonyl chlor-
ides were either unavailable or very costly were also possible by route 2.
For example, the compounds, 7d and 7i–7m would require trisubstituted
benzenesulfonyl chlorides by route 1, which were not readily available.
However, these compounds were easily possible by route 2 through
simple disubstituted benzenesulfonyl chlorides. As can be envisaged,
route 1 also offered the possibility of the formation of other Heck pro-
ducts by cyclization through C2 of indole and in fact that is the most
favored end product thermodynamically as well as sterically. It was
therefore not possible to synthesize the compounds 7 by route 1 without
any substitution at C2 of indole. However, these compounds were easily
possible by route 2. The Heck reaction was carried out using various
palladium(0) catalysts; however, the Tetrakis triphenyl phosphine
palladium(0) was found to be best suited for this intramolecular cycliza-
tion. Typically, the reactions were carried out with 0.03 to 0.05 mol% of
the catalyst. The reaction was also tried in various polar aprotic solvents
in combination with a variety of bases. However, the combination of pot-
assium acetate as base and N,N-dimethyl acetamide as solvent was found
to be the best. Typically, with this combination, the reactions were com-
pleted at 90–100 ꢁC within 3 to 5 h. The better reaction yields and the
improved rate of reaction could be due to the difference in the stability
of intermediate palladium complex. The palladium complex at C7 could
be sterically unstable as compared to the one at ortho position of the
arylsulfonyl moiety.

2422
R. Kambhampati et al.
EXPERIMENTAL
Commercial reagents were utilized without further purification. Room
temperature refers to 25–30 ꢁC. Melting points are uncorrected. IR spec-
tra were taken using KBr and in solid state. All mass spectra were carried
out using ESI conditions. 1H NMR spectra were recorded at 400 MHz on
a Bruker instrument in CDCl3 using TMS as internal reference standard,
and chemical shifts are expressed in d (ppm) values. CHN analysis was
carried out on an Elementar, Vario EL model. Chromatography refers
to column chromatography performed using 60- to 120-mesh silica gel
executed under nitrogen pressure (flash chromatography) conditions.
Reaction of 4 with Aromatic Sulfonyl/Carbonyl/Methyl Chlorides
(General Procedure)
A THF solution of 4 (0.01 mol) was added dropwise to a cooled suspen-
sion of KH (0.011 mol, washed with n-hexane before use) in dry THF.
The reaction mixture was brought to rt and stirred for 2 h. It was cooled
once again, and an appropriate sulfonyl=carbonyl=methyl chloride
(0.011 mol, dissolved in THF) was added dropwise. After completion
of the reaction (TLC, 5 h), it was poured on ice-cold water and extracted
with ethyl acetate. The combined organic layer was washed with water,
dried over sodium sulphate, and concentrated under vacuum afford
5 or 6 after purification over silica gel. All the synthesized compounds
were purified and fully characterized. Spectral data of some of the selec-
ted compounds are given here.
Data
1-Benzene sulfonyl-7-bromo-3-(N,N-dimethylamino ethyl)-1H-indole (6a):
IR (KBr, cmꢀ1): 2942, 2768,þ1447, 1360, 1265, 1173, 1124, 965, 685; mass
1
˙
(m=z): 407.3, 409.2 (M þ H) ; H NMR (d ppm): 2.35 (6H, s), 2.63–2.67
(2H, m), 2.85–2.89 (2H, m), 7.07–7.09 (1H, t, J ¼ 7.74 Hz), 7.43–7.49
(4H, m), 7.55–7.60 (1H, m), 7.71 (1H, s), 7.70–7.82 (2H, m). Anal. calcd.
for C18H19BrN2O2S: C, 53.08; H, 4.70; N, 6.88. Found: C, 53.19; H, 4.78;
N, 6.99.
1-Benzyl-7-bromo-3-(N,N-dimethylamino ethyl)-2-methyl-5-methoxy-
1H-indole (6n): IR (KBr, cmꢀ1): 2951, 2733, 1606, 1489, 1375, 1288,
þ
1
˙
1033, 790, 679; mass (m=z): 401.2, 403.2 (M þ H) ; H NMR (d ppm):
2.27 (3H, s), 2.37 (6H, s), 2.52–2.56 (2H, m), 2.93–2.97 (2H, m), 3.91
(3H, s), 5.1 (2H, s), 7.2–7.4 (5H, m), 7.55–7.69 (2H, m). Anal. calcd. for
C21H25BrN2O: C, 62.85; H, 6.28; N, 6.98. Found: C, 62.97; H, 6.37; N, 6.91.

Rigid Analogs of Tryptamine
2423
1-Benzoyl-7-bromo-3-(N,N-dimethylamino ethyl)-2-methyl-5-methoxy-
1H-indole (6t): IR (KBr, cmꢀ1): 2945, þ1668, 1428, 1330, 1151, 960, 795,
1
˙
680; mass (m=z): 415.3, 417.3 (M þ H) ; H NMR (d ppm): 2.3 (3H, s),
2.44 (6H, s), 2.44–2.59 (2H, m), 2.77–2.88 (2H, m), 3.93 (3H, s), 7.29–
7.52 (5H, m), 7.58–7.83 (2H, m). Anal. calcd. for C21H23BrN2O2: C,
60.73; H, 5.58; N, 6.74. Found: C, 60.65; H, 5.67; N, 6.83.
General Procedure for Synthesis of Compounds 7
A mixture of 1-(substituted benzene sulfonyl=carbonyl=methyl)-7-bromo
indole derivative (0.368 mmol), tetrakis triphenylphosphine palladium(0)
(0.022 mmol), and potassium acetate (0.55 mmol) in dimethyl acetamide
(4 mL) was heated to 90–100 ꢁC under a nitrogen atmosphere. After com-
pletion of the reaction (3 h, TLC), it was cooled to 25 ꢁC and filtered over
hyflow. The filtrate was diluted with ice water, pH was adjusted to 9–10
with aqueous potassium hydroxide solution, and the product was
extracted with (2 ꢂ 50 mL) ethyl acetate. The combined organic extracts
were washed with brine, dried over anhydrous sodium sulfate, and
concentrated under vacuum. The crude residue was purified by column
chromatography using silica gel (100–200 mesh), the eluent system being
ethyl acetate and triethylamine in 99.5 : 0.5 ratio, to obtain the desired
product.
Data
3-(N,N-Dimethylaminoethyl)-1,2-benzothiazino[2,3,4-ab]indole-S,S-dioxide
(7a): IR (KBr,þcmꢀ1): 2982, 1594, 1328, 1173, 1128, 756; mass (m=z):
1
˙
327.2 (M þ H) ; H NMR (d ppm): 2.35 (6H, s), 2.69–2.72 (2H, m),
2.97–3.01 (2H, m), 7.46–7.5 (1H, m), 7.59–7.64 (2H, m), 7.71–7.73 (1H,
d, J ¼ 7.72 Hz), 7.77 (1H, bm), 7.95–7.97 (1H, d, J ¼ 7.68 Hz), 8.17–
8.19 (1H, d, J ¼ 7.92 Hz), 8.22–8.24 (1H, dd, J ¼ 8.0, 0.96 Hz). Anal.
calcd. for C18H18N2O2S: C, 66.23; H, 5.56; N, 8.58. Found: C, 66.33;
H, 5.63; N, 8.52.
5-Chloro-8-fluoro-3-(N,N-dimethylaminoethyl)-1,2-benzothiazino[2,3,
4-ab]indole-S,S-dioxide (7b): IR (KBr, cmꢀþ1): 2763, 1603, 1330, 1174,
1
˙
1126, 865, 551; mass (m=z): 379.2 (M þ H) ; H NMR (d ppm): 2.34
(6H, s), 2.66–2.7 (2H, t), 2.93–2.96 (2H, m), 7.34–7.38 (1H, m), 7.63
(1H, s), 7.72 (1H, d, J ¼ 1.52 Hz), 7.77–7.8 (1H, dd, J ¼ 9.4 Hz),
7.863–7.866 (1H, d, J ¼ 1.28 Hz), 8.22–8.26 (1H, dd, J ¼ 8.6 Hz). Anal.
calcd. for C18H16ClFN2O2S: C, 57.07; H, 4.26; N, 7.39. Found: C, 57.19;
H, 4.37; N, 7.47.

2424
R. Kambhampati et al.
3-(N,N-Dimethylaminoethyl)-5,8-diflꢁuoro-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7c): Melting range ( C): 150–152.5; IR (KBr, cmꢀ1):
2976, 16þ02, 1474, 1336, 1173, 1134, 860, 662, 539; mass (m=z): 363.3
1
˙
(M þ H) ; H NMR (d ppm): 2.34 (6H, s), 2.66–2.7 (2H, m), 2.92–2.96
(2H, m), 7.35 (1H, m), 7.43–7.45 (1H, dd, J ¼ 8.52 Hz), 7.59–7.62 (1H,
dd, J ¼ 9.6 Hz), 7.64 (1H, s), 7.72–7.75 (1H, dd, J ¼ 9.4 Hz), 8.22–8.26
(dd, 1H, J ¼ 8.8 Hz). Anal. calcd. for C18H16F2N2O2S: C, 59.66; H,
4.45; N, 7.73. Found: C, 59.81; H, 4.51; N, 7.84.
3-(N,N-Dimethylaminoethyl)-9,10-dichloro-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7d): Melting range (ꢁC): >240; IR (KBr, cmꢀ1): 2940,
þ
1
˙
1448, 1329, 1165, 793, 600; mass (m=z): 394.9, 397 (M þ H) ; H NMR (d
ppm): 2.37 (6H, s), 2.71–2.75 (2H, m), 3.00–3.03 (2H, m), 7.45–7.49 (1H, t),
7.74–7.76 (1H, d, J ¼ 7.72Hz), 7.81–7.83 (1H, d, J ¼ 8.76Hz), 7.89–7.91
(1H, d, J ¼ 7.76Hz), 8.08–8.10 (1H, d, J ¼ 8.72Hz). Anal. calcd. for
C18H16Cl2N2O2S: C, 54.69; H, 4.08; N, 7.09. Found: C, 54.58; H, 4.16;
N, 6.99.
8-Methyl-3-(N,N-dimethylaminoethyl)-1,2-benzothiazino[2,3,4-ab]indole-
þ
1
˙
S,S-dioxide (7e): Mass (m=z): 341.2 (M þ H) ; H NMR (d ppm): 2.36
(6H, s), 2.56 (3H, s), 2.69–2.73 (2H, t), 2.97–3.01 (2H, t), 7.41–7.49 (2H,
m), 7.58 (1H, s), 7.7–7.72 (d, 1H, J ¼ 7.8 Hz), 7.94–7.96 (d, 1H,
J ¼ 7.68 Hz), 7.981 (1H, s), 8.1–8.12 (d, 1H, J ¼ 8.12Hz). Anal. calcd.
for C19H20N2O2S: C, 67.03; H, 5.92; N, 8.23. Found: C, 67.19; H, 5.85;
N, 8.16.
8-Isopropyl-3-(N,N-dimethylaminoethyl)-1,2-benzothiazino[2,3,4-ab]-
þ
1
˙
indole-S,S-dioxide (7f): Mass (m=z): 369.4 (M þ H) ; H NMR (d ppm):
1.355–1.372 (6H, d, J ¼ 6.96 Hz), 2.35 (6H, s), 2.69–2.73 (2H, m), 2.97–
3.01 (2H, m), 3.09–3.12 (1H, septet, J ¼ 6.92 Hz), 7.45–7.49 (2H, m),
7.58 (1H, s), 7.7–7.72 (dd, 1H, J ¼ 7.8 Hz), 7.98–7.99 (1H, d,
J ¼ 7.64 Hz), 8.00–8.01 (1H, d, J ¼ 1.52 Hz), 8.13–8.16 (1H, d,
J ¼ 8.24 Hz). Anal. calcd. for C21H24N2O2S: C, 68.45; H, 6.56; N,
7.60. Found: C, 68.59; H, 6.71; N, 7.67.
3-(N,N-Dimethylaminoethyl)-5-chloro-8-methoxy-1,2-benzothiazino-[2,
3,4-ab]indole-S,S-dioxide (7g): Melting range (ꢁC): 176.6–183; IR (KBr,
cmꢀ1): 2980, 1596, 1311, 1167, 850, 573, 534; mass (m=z): 391.1
þ
1
˙
(M þ H) ; H NMR (d ppm): 2.36 (6H, s), 2.67–2.71 (2H, m), 2.93–
2.97 (2H, m), 4.0 (3H, s), 7.13–7.16 (1H, dd, J ¼ 8.84, 2.36 Hz), 7.52–
7.53 (1H, d, J ¼ 2.36 Hz), 7.61 (1H, s), 7.68 (1H, d, J ¼ 1.56 Hz),
7.86–7.87 (1H, d, J ¼ 1.56 Hz), 8.13–8.16 (1H, d, J ¼ 8.84 Hz). Anal.
calcd. for C19H19ClN2O3S: C, 58.38; H, 4.90; N, 7.17. Found: C, 58.32;
H, 4.99; N, 7.28.
3-(N,N-Dimethylaminoethyl)-5-fluoro-8-isopropyl-1,2-benzothiazino-[2,
3,4-ab]indole-S,S-dioxide (7h): Melting range (ꢁC): 117–124; IR (KBr,
cmꢀ1): 2917, 1598, 1344, 1178, 1128, 796, 661; mass (m=z): 387 (M þ H)þ ;

Rigid Analogs of Tryptamine
2425
1
˙
; H NMR (d ppm): 1.35–1.37 (6H, d), 2.36 (6H, s), 2.68–2.72 (2H, m),
2.93–2.97 (2H, m), 3.1–3.13 (1H, sep), 7.38–7.4 (1H, dd, J ¼ 8.56,
2.1 Hz), 7.51–7.53 (1H, dd, J ¼ 8.28, 1.56 Hz), 7.63 (1H, s), 7.68–7.71
(1H, dd, J ¼ 9.9, 2.08 Hz), 7.914–7.918 (1H, d, J ¼ 1.48 Hz), 8.14–8.16
(1H, d, J ¼ 8.28 Hz). Anal. calcd. for C21H23FN2O2S: C, 65.26; H, 6.00;
N, 7.25. Found: C, 65.34; H, 5.93; N, 7.37.
3-(N,N-Dimethylaminoethyl)-8,10-difluoro-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7i): Melting range (ꢁC): 155–160; IR (KBr, cmꢀ1): 2963,
1612, 1331, 1261, 1173, 1111, 855, 797, 512; mass (m=z): 363.1 (M þ H)þ;
1
˙
H NMR (d ppm): 2.41 (6H, s), 2.74–2.78 (2H, m), 3.02–3.06 (2H, m),
7.04–7.1 (1H, m), 7.47–7.53 (1H, t), 7.62 (1H, s), 7.67–7.71 (1H, m), 7.8–
7.82 (1H, d, J ¼ 7.76Hz), 7.87–7.89 (1H, d, J ¼ 7.72Hz). Anal. Calcd.
for C18H16F2N2O2S: C, 59.66; H, 4.45; N, 7.73. Found: C, 59.79; H,
4.57; N, 7.81.
3-(N,N-Dimethylaminoethyl)-7-trifluoromethyl-10-chloro-1,2-benzothi-
azino-[2,3,4-ab]indole-S,S-dioxide (7j): IR (KBr, cmꢀ1): 2917, 1348,
þ
1
˙
1297, 1170, 1142, 753; mass (m=z): 429.1, 431 (M þ H) ; H NMR (d
ppm): 2.37 (6H, s), 2.72–2.76 (2H, m), 2.99–3.04 (2H, m), 7.48–7.58
(2H, m), 7.72–7.82 (2H, m), 8.20–8.60 (2H, m). Anal. calcd. for
C19H16ClF3N2O2S: C, 53.21; H, 3.76; N, 6.53. Found: C, 53.27; H,
3.85; N, 6.61.
3-(N,N-Dimethylaminoethyl)-5-fluoro-7-trifluoromethyl-10-chloro-1,2-
benzothiazino-[2,3,4-ab]indole-S,S-dioxide (7k): IR (KBr, cmꢀ1): 2943,
1435, 1349, 1298, 1170, 868; mass (m=z): 447.2, 449.2 (M þ H)þ; 1H
˙
NMR (d ppm): 2.36 (6H, s), 2.69–2.73 (2H, m), 2.94–2.98 (2H, m),
7.46–7.49 (1H, dd, J ¼ 8.0, 2.1 Hz), 7.54 (1H, s), 7.76–7.78 (1H, d,
J ¼ 8.72 Hz), 7.79–7.82 (1H, dd), 8.04–8.07 (1H, d, J ¼ 8.60 Hz). Anal.
calcd. for C19H15ClF4N2O2S: C, 51.07; H, 3.38; N, 6.27. Found: C,
51.19; H, 3.33; N, 6.38.
3-(N,N-Dimethylaminoethyl)-5,9,10-trichloro-1,2-benzothiazino-[2,3,
4-ab]indole-S,S-dioxide (7l): Melting range (ꢁC): 210.4–214.9; IR (KBr,
cmꢀ1): 2946, 1445, 1339, 1163, 838, 594, 568; mass (m=z): 429.1,
1
431.1, 432.9 (M þ H)þ; H NMR (d ppm): 2.35 (6H, s), 2.67–2.71
(2H, m), 2.93–2.97 (2H, m), 7.66 (1H, s), 7.70–7.71 (1H, d, J ¼ 1.48 Hz),
Hz), 7.83–7.86 (2H, m), 8.01–8.03 (1H, d, J ¼ 8.76 Hz). Anal. calcd.
for C18H15Cl3N2O2S: C, 50.31; H, 3.52; N, 6.52. Found: C, 50.19; H,
3.59; N, 6.43.
˙
3-(N,N-Dimethylaminoethyl)-5-fluoro-9,10-dichloro-1,2-benzothiazino-
[2,3,4-ab]indole-S,S-dioxide (7m): Melting range (ꢁC): 207–210; IR
(KBr, cmꢀ1): 2918, 1454, 1340, 1175, 1163, 838, 581; mass (m=z): 413.2,
1
415.2 (M þ H)þ; H NMR (d ppm): 2.35 (6H, s), 2.66–2.70 (2H,
m), 2.92–2.96 (2H, m), 7.41–7.44 (1H, dd, J ¼ 8.4, 2.12 Hz), 7.59–7.62
(1H, dd, J ¼ 9.98, 2.0 Hz), 7.68 (1H, s), 7.83–7.85 (1H, d, J ¼ 8.78 Hz),
˙

2426
R. Kambhampati et al.
7.97–7.99 (1H, d, J ¼ 8.78 Hz). Anal. calcd. for C18H15Cl2FN2O2S: C,
52.31; H, 3.66; N, 6.78. Found: C, 52.45; H, 3.73; N, 6.71.
[2-(2-Methoxy-5-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-4-yl)ethyl]
dimethylamine (7n): IR (KBr, cmꢀ1): 2942, 2761, 1601, 1498, 1486, 1375,
þ
1
˙
1294, 1029; mass (m=z): 321.2 (M þ H) ; H NMR (d ppm): 2.37 (6H, s),
2.52–2.60 (2H, m), 2.84–2.96 (5H, m), 3.97 (3H, s), 5.35 (2H, s), 7.2–7.6
(5H, m), 7.64–7.77 (1H, m). Anal. calcd. for C21H24N2O: C, 78.71; H,
7.55; N, 8.74. Found: C, 78.83; H, 7.67; N, 8.67.
[2-(2-Chloro-5-methyl-7H-pyrrolo[3,2,1-de]phenanthridin-4-yl)ethyl]-
dimethylamine (7o): IR (KBr, cmꢀ1): 2939, 27þ63, 1494, 1449, 1376, 1263,
1
˙
834, 770; mass (m=z): 325.2, 327.1 (M þ H) ; HNMR (d ppm): 2.35
(9H, bs), 2.45–2.53 (2H, m), 2.81–2.89 (2H, m), 5.36 (2H, s), 7.19–
7.35 (5H, m), 7.81–7.84 (1H, m). Anal. calcd. for C20H21ClN2: C,
73.95; H, 6.52; N, 8.62. Found: C, 74.12; H, 6.61; N, 8.69.
3-(N,N-Dimethylaminoethyl)-5,8-dichloro-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7p): Melting range (ꢁC): 101–108; IR (KBr, cmꢀ1):
2982, 2769, 1329, 1178, 1150, 851, 791, 619, 529; mass (m=z): 395, 397,
1
399 (M þ H)þ ; H NMR (d ppm): 2.35 (6H, s), 2.67–2.71 (2H, m),
2.93–2.97 (2H, m), 7.61–7.64 (2H, m), 7.72 (1H, s), 7.89–7.90 (1H, d,
J ¼ 1.52 Hz), 8.09–8.10 (1H, d, J ¼ 1.56 Hz), 8.15–8.17 (1H, d,
J ¼ 8.56 Hz). Anal. calcd. for C18H16Cl2N2O2S: C, 54.69; H, 4.08; N,
7.09. Found: C, 54.81; H, 4.16; N, 7.13.
˙
3-(N,N-Dimethylaminoethyl)-5-fluoro-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7q): Melting range (ꢁC): 126–129; IR (KBr, cmꢀ1):
2953, 1461, 1333, 1173, 1138, 765, 561; mass (m=z): 345.3 (M þ H)þ;
1
˙
H NMR (d ppm): 2.35 (6H, s), 2.67–2.71 (2H, m), 2.92–2.96 (2H,
m), 7.38–7.41 (1H, dd, J ¼ 8.56, 2.08 Hz), 7.64–7.69 (3H, m), 7.78–
7.8 (1H, m), 8.09–8.11 (1H, d, J ¼ 7.92 Hz), 8.22–8.25 (1H, dd,
J ¼ 7.92, 1 Hz). Anal. calcd. for C18H17FN2O2S: C, 62.77; H, 4.98;
N, 8.13. Found: C, 62.89; H, 5.07; N, 8.21.
5-Chloro-3-(N,N-dimethylaminoethyl)-1,2-benzothiazino-[2,3,4-ab]-
indole-S,S-dioxide (7r): Melting range (ꢁC): 133–136.3; IR (KBr, cmꢀ1
)
: 2962, 1331, 1169, 1124, 826, 766, 749; mass (m=z): 361, 363 (M þ H)þ;
1
˙
H NMR (d ppm): 2.35 (6H, s), 2.67–2.71 (2H, m), 2.93–2.97 (2H, m),
7.62–7.69 (3H, m), 7.78–7.80 (1H, m), 7.92–7.93 (1H, d, J ¼ 1.56 Hz),
8.12–8.14 (1H, d), 8.22–8.24 (1H, dd, J ¼ 8.0, 1.08 Hz). Anal. calcd.
for C18H17ClN2O2S: C, 59.91; H, 4.75; N, 7.76. Found: C, 59.83; H,
4.86; N, 7.67.
4-(2-Dimethylamino ethyl)-2-fluoro-5-methyl pyrrolo[3,2,1-de]phenan-
thridin-7-one (7s): IR (KBr, cmꢀþ1): 2945, 1688, 1463, 1353, 1143, 1118,
1
˙
765; mass (m=z): 323.3 (M þ H) ; H NMR (d ppm): 1.68 (3H, s), 2.25
(6H, s), 3.0–3.2 (2H, m), 3.3–3.43 (2H, m), 6.9–7.48 (4H, m), 7.54–7.66

Rigid Analogs of Tryptamine
2427
(2H, m). Anal. calcd. for C20H19FN2O: C, 74.51; H, 5.94; N, 8.69.
Found: C, 74.65; H, 6.03; N, 8.81.
4-(2-Dimethylamino ethyl)-2-methoxy-5-methyl pyrrolo[3,2,1-de]phe-
nanthridin-7-one (7t): IR (KBr, cmꢀ1)þ: 2933, 1662, 1461, 1333, 1151,
1
˙
1157, 795; mass (m=z): 335.3 (M þ H) ; H NMR (d ppm): 2.36 (3H,
s), 2.41 (6H, s), 2.41–2.6 (2H, m), 2.81–2.93 (2H, m), 3.85 (3H, s),
7.23–7.66 (5H, m), 7.68–7.74 (1H, m). Anal. calcd. for C21H22N2O2: C,
75.42; H, 6.63; N, 8.38. Found: C, 75.59; H, 6.72; N, 8.47.
ACKNOWLEDGMENTS
Authors acknowledge the support received from Venkateswarlu Jasti,
CEO, Suven Life Sciences Ltd., and Discovery Analytical Department
staff for their expert analytical assistance.
REFERENCES
1. Heck, R. F. Arylation, methylation, and carboxyalkylation of olefins by
Group VIII metal derivatives. J. Am. Chem. Soc. 1968, 90, 5518–5526; (b)
Heck, R. F. The arylation of allylic alcohols with organopalladium com-
pounds. A new synthesis of 3-aryl aldehydes and ketones. J. Am. Chem.
Soc. 1968, 90, 5526–5531; (c) Heck, R. F. Allylation of aromatic compounds
with organopalladium salts. J. Am. Chem. Soc. 1968, 90, 5531–5534; (d)
Heck, R. F. The palladium-catalyzed arylation of enol esters, ethers, and
halides. A new synthesis of 2-aryl aldehydes and ketones. J. Am. Chem.
Soc. 1968, 90, 5535–5538; (e) Heck, R. F. Aromatic haloethylation with pal-
ladium and copper halides. J. Am. Chem. Soc. 1968, 90, 5538–5542; (f) Heck,
R. F. The addition of alkyl- and arylpalladium chlorides to conjugated
dienes. J. Am. Chem. Soc. 1968, 90, 5542–5546; (g) Heck, R. F. A synthesis
of diaryl ketones from arylmercuric salts. J. Am. Chem. Soc. 1968, 90, 5546–
5548.
2. Heck, R. F. The mechanism of arylation and carbomethoxylation of
olefins with organopalladium compounds. J. Am. Chem. Soc. 1969, 91,
6707–6714.
3. Heck, R. F. Palladium-Catalysed Vinylation of Organic Halides. Organic
Reactions Inc. N.Y. 1982; Vol. 27, pp 345.
4. Plevyak, J. E.; Heck, R. F. Palladium-catalyzed arylation of ethylene. J. Org.
Chem. 1978, 43, 2454–2456.
5. Braese, S.; Gil, C.; Knepper, K. The recent impact of solid-phase synthesis on
medicinally relevant benzoannelated nitrogen heterocycles. Bioorg. Med.
Chem. 2002, 10(8), 2415–2438; (b) Amos, P. C.; Whiting, D. A. Palladium-
Catalyzed intramolecular arylation: a new synthesis of Munduserone. J. Chem.
Soc. Chem. Commun. 1987, 510–511.

2428
R. Kambhampati et al.
6. Ramakrishna V. S. Nirogi; Kambhampati, R. S.; Shirsath, V. S.; Jasti V.
Benzothiazino indoles, WO2005=005439 A1; International filling date 7-Jul-2004.
7. Timur, G.; Patrice, M.; Jean-Marie, T.; Francoise, C.; Joelle, M.; Francoise,
H.; Virone-Oddos, A.; Francois, C.; Alix, C. N6-Substituted Adenosine
Receptor Agonists. Synthesis and Pharmacological Activity as Potent Antino-
ciceptive Agents. J. Med. Chem. 1994, 37, 4307–4316.