Syntheses of fused tetrahydro-β-carboline analogues through imide carbonyl activation using BBr3: Evidence for the involvement of fused cyclic N-acyliminium ion intermediate

Article abstract of DOI:10.1007/s12039-015-0836-8

Abstract The fused cyclic N-acyliminium ion generated during the imide carbonyl activation reaction of phenethylphthalimide was confirmed by single crystal X-ray diffraction. The Lewis acid assisted imide carbonyl activation methodology was successfully extended to synthesize fused tetrahydro-β-carboline units from the corresponding N-indolylethylimides. [Figure not available: see fulltext.]

Full text of DOI:10.1007/s12039-015-0836-8

c
J. Chem. Sci. Vol. 127, No. 5, May 2015, pp. 811–819. ꢀ Indian Academy of Sciences.
DOI 10.1007/s12039-015-0836-8
Syntheses of fused tetrahydro-β-carboline analogues through imide
carbonyl activation using BBr3: Evidence for the involvement of fused
cyclic N-acyliminium ion intermediate
SELVARAJ MANGALARAJ, JAYARAMAN SELVAKUMAR,
and CHINNASAMY RAMARAJ RAMANATHAN∗
Department of Chemistry, Pondicherry University, Puducherry 605 014, India
e-mail: crrnath.che@pondiuni.edu.in
MS received 12 September 2014; revised 09 January 2015; accepted 10 January 2015
Abstract. The fused cyclic N-acyliminium ion generated during the imide carbonyl activation reaction of
phenethylphthalimide was confirmed by single crystal X-ray diffraction. The Lewis acid assisted imide car-
bonyl activation methodology was successfully extended to synthesize fused tetrahydro-β-carboline units from
the corresponding N-indolylethylimides.
Keywords. Intramolecular cyclization; fused cyclic N-acyliminium ion; tetrahydro-β-carboline; BBr3.
1. Introduction
conclusion that the involvement of fused cyclic N-
acyliminium ion as intermediate which are potential to
accept various nucleophiles.13 Though fused cyclic N-
acyliminium ions were known for a decade in the liter-
ature, they have not been confirmed spectroscopically
until recently.14 Hence, we have initiated our effort to
ascertain the structure of intermediate in Lewis acid
assisted phenethylimide cyclization reaction and fur-
ther extend the methodology to synthesize tetrahydro-
β-carboline derivatives.
Alkaloids possessing tetrahydro-β-carboline (THBC)
framework exhibits a wide spectrum of biological
activities.1 Fused indole alkaloids such as pyrrolo-
β-carbolines, indolo[a]quinolizine and isoindolo-β-
carboline units were found in various alkaloids and
therapeutic agents (figure 1).1b
These tetrahydro-β-carboline scaffolds are usually
assembled through Bischler-Napieralski,2 N-acyliminium
ion,3 RCM/isomerization/N-acyliminium ion cyclization,4
Pictet-Spengler/Michael addition,5 Pictet-Spengler/N-
acyliminiumion cyclization,6 radical coupling,7 cascade
goldcatalysis,8 aza Diels-Alderreaction,9 dipolar cycload-
dition10 and intra-molecular Michael addition reaction.11
Due to the presence of structural diversity and com-
plexity as well as the range of biological activity, the
development of new synthetic methodology with a sim-
ple reagent or catalyst is always desirable for the fused
tetrahydro-β-carboline skeleton. Our interest in the devel-
opment of Lewis acid/Brønsted acid catalysis chemistry
led us to develop the efficient protocol for the synthesis
of tetrahydroisoquinoline, tetrahydro-β-carboline and
related alkaloids as well as library of carbinols.12 Pre-
viously, we have disclosed the first single step conversion
of phenethylimides to corresponding tetrahydroiso-
quinoline scaffolds using boron tribromide and we have
investigated the intermediate involved in this proto-
2. Experimental
2.1 General Information
Melting points reported in this work are uncorrected
and were determined using EZ Melt, Stanford Research
Systems, USA. Infrared spectra were recorded on
Thermo Nicolet 6700 FT-IR Spectrophotometer using
potassium bromide thin films and are reported in fre-
quency of absorption (cm−1). High resolution mass
spectra (HRMS) were recorded on Q-TOF Micro mass
spectrometer. 1H and 13C NMR were recorded on
Brucker AVANCE 400 spectrometer. All the NMR
spectra were recorded at room temperature in CDCl3
or DMSO-d6 using TMS as an internal standard. The
chemical shifts are expressed in δ ppm down field from
the signal of internal TMS. X-ray crystal data were col-
lected on Oxford Diffraction Xcalibur diffractometer
with Mo-Kα radiation (λ = 0.71073 Å). All the chem-
icals and reagents were purchased from Sigma Aldrich
1
col using H-NMR analysis.12a This study leads to the
∗For correspondence
811

812
Selvaraj Mangalaraj et al.
Figure 1. Condensed THBC - core containing alkaloids and drugs.
(Lit.16 163–166◦C); IR (KBr, cm−1): 3265, 3052, 2925,
1764, 1694, 1401, 1339; 1H NMR (400 MHz, CDCl3):
δ 8.04 (br s, 1H), 7.66 (d, J = 8.0 Hz, 1H), 7.34
(d, J = 8.0 Hz, 1H), 7.19 (t, J = 7.6 Hz, 1H), 7.13
(t, J = 7.6 Hz, 1H), 7.08 (d, J = 1.9 Hz, 1H), 3.83
(t, J = 7.6 Hz, 2H), 3.06 (t, J = 7.6 Hz, 2H), 2.61
(s, 4H); 13C NMR (100 MHz, CDCl3): 177.38, 136.29,
127.64, 122.27, 122.23, 119.67, 118.77, 112.41,
111.30, 39.65, 28.29, 23.45.
Chemicals and used without further purification. Col-
umn chromatography was performed using either silica
gel 100–200 mesh (Merck, India) or neutral alumina
(AVRA, India). TLC analyses were facilitated using
KMnO4 stain in addition to UV light with Merck 60
F254 pre-coated silica plates.
2.2 General procedure for the preparation of
indolylethylimide derivatives15
Suspensionof anhydride (18.725 mmol) in toluene in an
oven dried round-bottom flask fitted with Dean-Stark
set up was heated at reflux until complete dissolution
of the anhydride and no additional water was removed.
To this solution was added tryptamine (3.000 g, 18.725
mmol) and refluxing was continued until the water evo-
lution was completed (12 h). Reaction mixture was con-
centrated under reduced pressure to give a residue which
was purified through neutral alumina column chroma-
tography using ethyl acetate:hexane as eluent (1:4).
2.2c 1-(2-(1H-Indol-3-yl)ethyl)piperdine-2,6-dione (3d):
6e3.215 g, tan solid, 67% yield; M.p. 174–175◦C, IR
(KBr, cm−1): 3333, 2971, 2958, 1718, 1665, 1456,
1
1354; H NMR (400 MHz, CDCl3): δ 8.02 (br s, 1H),
7.77 (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H),
7.20–7.12 (m, 2H), 7.06 (d, J = 1.7 Hz, 1H), 4.07
(t, J = 8.0 Hz, 2H), 2.98 (t, J = 8.0 Hz, 2H), 2.61
(t, J = 6.4 Hz, 4H), 1.87 (p, J = 6.4 Hz, 2H); 13C NMR
(100 MHz, CDCl3): 172.67, 136.27, 127.78, 122.25,
122.13, 119.56, 119.25, 113.06, 111.17, 40.45, 32.99,
23.84, 17.26.
2.2a 2-(2-(1H-Indol-3-yl)ethyl)isoindoline-1,3-dione
(3a): 4.250 g, yellow solid, 78%, yield; M.p. 166–
167◦C (Lit.15 166–168◦C); IR (KBr, cm−1): 3383, 3044,
1
2942, 2858, 1767, 1703, 1233; H NMR (400 MHz,
2.2d 2-(2-(1H-Indol-3-yl)ethyl)hexahydro-1H-isoindole-
1,3(2H)-dione (3e): 3.496 g, pale orange solid, 63%
yield; M.p. 145–146◦C; IR (KBr, cm−1): 3364, 2944,
CDCl3): δ 8.05 (br s, 1H), 7.83 (dd, J = 5.4, 3.0 Hz,
2H), 7.74 (dt, J = 8.0, 0.8 Hz, 1H), 7.70 (dd, J = 5.4,
3.0 Hz, 2H), 7.34 (dt, J = 7.6, 0.8 Hz, 1H), 7.19 (td,
J = 7.6, 1.2 Hz, 1H), 7.13 (td, J = 8.0, 1.2 Hz, 1H),
7.08 (d, J = 2.4 Hz, 1H), 4.04–3.99 (m, 2H), 3.19–3.15
(m, 2H); 13C NMR (100 MHz, CDCl3): 168.51, 136.37,
134.00, 132.34, 127.55, 123.31, 122.27, 122.14,
119.66, 119.01, 112.59, 111.24, 38.66, 24.60.
1
2860, 1766, 1694, 1401, 1341; H NMR (400 MHz,
CDCl3): δ 8.02 (br s, 1H), 7.69 (d, J = 7.6 Hz, 1H),
7.34 (d, J = 8.0 Hz, 1H), 7.18 (t, J = 7.2 Hz, 1H),
7.15–7.11 (m, 1H), 7.07 (d, J = 1.8 Hz, 1H), 3.82
(t, J = 7.6 Hz, 2H), 3.07 (t, J = 7.6 Hz, 2H), 2.78–2.72
(m, 2H), 1.79–1.77 (m, 2H), 1.64–1.61 (m, 2H), 1.42–
1.31 (m, 4H); 13C NMR (100 MHz, CDCl3): 179.98,
136.25, 127.63, 122.28, 122.13, 119.55, 118.93,
2.2b 1-(2-(1H-Indol-3-yl)ethyl)pyrrolidine-2,5-dione
(3b): 3.211 g, tan solid, 71% yield; M.p. 166–167◦C 112.17, 111.21, 39.73, 39.12, 23.69, 23.37, 21.62.

813
21.71, 21.59, 16.65. HRMS (ESI): [M+H]+ Found
2.3 General procedure for the preparation of
substituted indolyl-ethylimide derivatives17,12d
325.1910 and calculated 325.1838 for C20H24N2O2.
A mixture of hydrazine hydrochloride (1 mmol) and
masked aldehyde (1 mmol) in 100 mL of 4% H2SO4
was heated at reflux for 12 h. The reaction mixture was
cooled to room temperature and treated with aqueous
NaHCO3. The tryptamine product was extracted with
CH2Cl2 (4 x 50 mL). The combined organic layer was
dried over anhydrous Na2SO4, filtered and the solvent
was evaporated under reduced pressure. The residue
was purified through neutral alumina column chro-
matography using ethyl acetate:hexane (1:4) as eluent
to give indolyl imides 3c, 3f–k as solid.
2.3d 2-(2-(5-Fluoro-1H-indol-3-yl)ethyl)hexahydro-1H-
isoindole-1,3(2H)-dione (3h): 264 mg, colourless
solid, 84% yield; M.p. 156–157◦C; FT-IR (KBr, cm−1):
3367, 2943, 2860, 1766, 1693, 1489, 1406, 1265, 1164,
1
800; H NMR (400 MHz, CDCl3): δ 8.05 (br s, 1H),
7.31 (dd, J = 9.6, 2.4 Hz, 1H), 7.24 (t, J = 4.4 Hz, 1H),
7.11 (d, J = 2.4 Hz, 1H), 6.92 (td, J = 8.8, 2.4 Hz,
1H), 3.81-3.78 (m, 2H), 3.01 (td, J = 7.6, 0.4 Hz, 2H),
2.78-2.75 (m, 2H), 1.81-1.76 (m, 2H), 1.64-1.60 (m,
2H), 1.43-1.37 (m, 2H), 1.35-1.25 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 179.93, 158.00 (d, J = 234.0 Hz,
1C), 132.73, 128.14 (d, J = 9.0 Hz, 1C), 124.05,
112.61 (d, J = 4.0 Hz, 1C), 111.84 (d, J = 9.0 Hz, 1C),
110.66 (d, J = 27.0 Hz, 1C), 103.95 (d, J = 23.0 Hz,
1C), 39.79, 38.95, 23.75, 23.31, 21.68. HRMS (ESI):
[M+H]+ Found 315.1496 and calculated 315.1431 for
C18H20FN2O2.
2.3a 1-(2-(5,7-Dimethyl-1H-indol-3-yl)ethyl)pyrrolidine-
12d
2,5-dione (3c):
148 mg, pale yellow solid, 55%
yield; M.p. 192–193◦C; IR (KBr, cm−1): 3348, 3125,
2860, 1769, 1691, 1405, 1264; H NMR (400 MHz,
1
CDCl3): δ 7.84 (br s, 1H), 7.28 (s, 1H), 7.05 (d, J =
2.2 Hz, 1H), 6.83 (s, 1H), 3.83–3.79 (m, 2H), 3.03–
3.00 (m, 2H), 2.62 (s, 4H), 2.43 (s, 6H); 13C NMR
(100 MHz, CDCl3) : 177.26, 134.09, 128.98, 127.27,
124.42, 121.95, 119.97, 115.88, 112.25, 39.58, 28.15,
23.47, 21.45, 16.51.
2.3e 2-(2-(5-Chloro-1H-indol-3-yl)ethyl)hexahydro-1H-
isoindole-1,3(2H)-dione(3i): 258 mg, pale yellow solid,
78% yield; M.p. 150–151◦C; FT-IR (KBr, cm−1): 3363,
1
2947, 2864, 1764, 1687, 1406, 1348; H NMR (400
2.3b 2-(2-(7-Methyl-1H-indol-3-yl)ethyl)hexahydro-
1H-isoindole-1,3(2H)-dione (3f): 164 mg, orange
solid, 53% yield; M.p. 190–191◦C; FT-IR (KBr, cm−1):
MHz, CDCl3): δ 8.06 (br s, 1H), 7.61 (d, J = 2.0 Hz,
1H), 7.25 (d, J = 8.4 Hz, 1H), 7.14 (dd, J = 8.4, 2.0
Hz, 2H), 7.10–7.00 (m, 1H), 3.79 (t, J = 7.6 Hz, 2H),
3.02 (td, J = 7.6, 0.8 Hz, 2H), 2.79–2.73 (m, 2H),
1.83-1.76 (m, 2H), 1.64–1.61 (m, 2H), 1.45–1.36 (m,
2H), 1.35–1.25 (m, 2H); 13C NMR (100 MHz, CDCl3):
δ 179.94, 134.56, 128.86, 125.48, 123.65, 122.59,
118.49, 112.30, 112.25, 39.77, 39.05, 23.73, 23.19,
21.67. HRMS (ESI): [M+H]+ Found 331.1203 and
calculated 331.1135 for C18H20ClN2O2.
1
3373, 2943, 2856, 1765, 1699, 1444, 1399, 1340; H
NMR (400 MHz, CDCl3): δ 7.94 (br, s, 1H), 7.54
(d, J = 7.6 Hz, 1H), 7.09–7.08 (m, 1H), 7.07–7.04 (m,
1H), 7.00–6.98 (m, 1H), 3.83-3.80 (m, 2H), 3.07–3.03
(m, 2H), 2.79–2.73 (m, 2H), 2.47 (s, 3H), 1.84–1.77
(m, 2H), 1.67–1.61 (m, 2H), 1.46–1.39 (m, 2H),
1.37–1.29 (m, 2H); 13C NMR (100 MHz, CDCl3):
δ 179.97, 135.87, 127.20, 122.77, 121.95, 120.35,
119.89, 116.77, 112.87, 39.79, 39.17, 23.77, 23.60,
21.70, 16.71. HRMS (ESI): [M+H]+ Found 311.1752
and calculated 311.1681 for C19H23N2O2.
2.3f 2-(2-(5-Bromo-1H-indol-3-yl)ethyl)hexahydro-1H-
isoindole-1,3(2H)-dione (3j): 255 mg, pale yellow
solid, 68% yield; M.p. 147–148◦C; FT-IR (KBr, cm−1):
1
2.3c 2-(2-(5,7-Dimethyl-1H-indol-3-yl)ethyl)hexahydro- 3336, 2934, 2858, 1773, 1691, 1344, 603; H NMR
1H-isoindole-1,3(2H)-dione (3g): 182 mg, pale (400 MHz, CDCl3): δ 8.08 (br s, 1H), 7.76 (d, J =
orange solid, 56% yield; M.p. 130–131◦C; FT-IR (KBr, 1.6 Hz, 1H), 7.24 (d, J = 1.6 Hz, 1H), 7.22–7.19 (m,
cm−1): 3357, 2929, 2857, 1769, 1699, 1403, 1261; 1H), 7.07 (d, J = 2.4 Hz, 1H), 3.79 (t, J = 3.6 Hz,
1H NMR (400 MHz, CDCl3): δ 7.84 (br s, 1H), 7.32 2H), 3.04–3.00 (m, 2H), 2.79–2.72 (m, 2H), 1.81–
(s, 1H), 7.04 (d, J = 2.3 Hz, 1H), 6.83 (s, 1H), 3.82- 1.76 (m, 2H), 1.64–1.60 (m, 2H), 1.45–1.38 (m, 2H),
3.78 (m, 2H), 3.04-3.00 (m, 2H), 2.78–2.76 (m, 2H), 1.35–1.29 (m, 2H); 13C NMR (100 MHz, CDCl3):
2.43 (s, 6H), 1.84–1.78 (m, 2H), 1.68-1.62 (m, 2H), δ 179.94, 134.84, 129.53, 125.13, 123.49, 121.58,
1.45–1.32 (m, 4H); 13C NMR (100 MHz, CDCl3): 112.98, 112.69, 112.25, 39.77, 39.07, 23.73, 23.17,
δ 179.97, 134.23, 129.15, 127.48, 124.57, 122.09, 21.66. HRMS (ESI): [M+H]+ Found 375.0691 and
120.01, 116.31, 112.43, 39.82, 39.25, 23.78, 23.62, calculated 375.0630 for C18H20BrN2O2.

814
Selvaraj Mangalaraj et al.
(100 MHz, CDCl3): 168.15, 142.88, 136.55, 132.56,
2.3g 2-(2-(7-Fluoro-1H-indol-3-yl)ethyl)hexahydro-
1H-isoindole-1,3(2H)-dione (3k): 192 mg, pale yellow 132.02, 128.90, 126.79, 124.51, 122.63, 122.10,
solid, 61% yield; M.p. 192–193◦C; FT-IR (KBr, cm−1): 120.09, 118.69, 111.07, 109.52, 57.02, 38.18, 21.66.
1
3352, 2947, 2860, 1769, 1704, 1432, 1341, 782; H
NMR (400 MHz, CDCl3): δ 8.22 (br, s, 1H), 7.44
2.4b 5,6,11,11b-Tetrahydro-1H-indolizino[8,7-b]indol-
(d, J = 7.6 Hz, 1H), 7.10 (d, J = 2.4 Hz, 1H), 7.03
3(2H)-one (4b): 38 mg, 84% yield, off white solid;
(td, J = 8.0, 4.8 Hz, 1H), 6.89 (dd, J = 11.2, 8.0 Hz,
1H), 3.83–3.79 (m, 2H), 3.07–3.04 (m, 2H), 2.79–
2.73 (m, 2H), 1.81–1.77 (m, 2H), 1.63–1.61 (m, 2H),
1.45–1.36 (m, 2H), 1.35–1.29 (m, 2H); 13C NMR
(100 MHz, CDCl3): δ 179.96, 149.69 (d, J = 242.0 Hz,
1C), 131.43 (d, J = 5.0 Hz, 1C), 124.59 (d, J = 14.0 Hz,
1C), 122.97, 119.91 (d, J = 6.0 Hz, 1C), 114.81
(d, J = 3.0 Hz, 1C), 113.22 (d, J = 2.0 Hz, 1C), 107.06
(d, J = 16.0 Hz, 1C), 39.78, 38.98, 23.75, 23.40, 21.68.
HRMS (ESI): [M+H]+ Found 315.1496 and calculated
315.1435 for C18H20FN2O2.
M.p. 251–252◦C (Lit.18 250◦C); IR (KBr, cm−1): 3253,
2978, 2848, 1664, 1454, 1311; H NMR (400 MHz,
1
CDCl3): δ 8.02 (br s, 1H), 7.50 (d, J = 8.0 Hz, 1H),
7.34 (dt, J = 8.0, 0.8 Hz, 1H), 7.23–7.16 (m, 1H),
7.16–7.09 (m, 1H), 4.94 (td, J = 6.9, 2.0 Hz, 1H),
4.54 (ddd, J = 12.9, 5.2, 1.8 Hz, 1H), 3.04 (dddd,
J = 12.9, 10.4, 6.0, 1.0 Hz, 1H), 2.89–2.82 (m, 2H),
2.63–2.5 (m, 3H), 2.01–1.89 (m, 1H); 13C-NMR
(100 MHz, CDCl3): 176.36, 136.41, 133.30, 126.96,
122.41, 120.05, 118.60, 111.12, 108.49, 54.41, 37.75,
31.78, 25.85, 21.18.
2.4 General procedure for BBr3 mediated cyclization
followed by NaBH4/ MeOH reduction
2.4c 8,10-Dimethyl-5,6,11,11b-tetrahydro-1H-indolizino
[8,7-b]indol-3(2H)-one (4c): 42 mg, 82% yield, pale
blue solid. M.p. 252–253◦C; IR (KBr, cm−1): 3263,
A 50 mL two-neck round-bottom flask was charged
with 3a–k (0.2 mmol, 1 equiv), 4Å molecular sieves
(50 mg), anhydrous CH2Cl2 (10 mL) and a stir bar.
The flask was capped with a rubber septum and main-
tained in nitrogen atmosphere. Boron tribromide (1 mL,
5 equiv or 2 mL, 10 equiv) was added and stirred at
room temperature for given time. To this reaction mix-
ture was added NaBH4 (5 equiv), methanol (3 mL) and
stirred for 30 min under nitrogen atmosphere. Then the
reaction mixture was quenched with aqueous NaHCO3.
Organic layer was separated and aqueous layer was
extracted with ethyl acetate (3 × 50 mL). The com-
bined organic layer was washed with aqueous NaHCO3,
dried over anhydrous Na2SO4 and filtered. The solvent
was removed under reduced pressure. The crude mix-
ture was purified through neutral alumina column chro-
matography using ethyl acetate:hexane (4:1) as eluent.
For the substrate 3a NaBH4/TFA was used as a reducing
mixture.
1
2916, 2851, 1665, 1436, 1366, 1267; H NMR (400
MHz, CDCl3): δ 7.72 (br, s, 1H), 7.13 (s, 1H), 6.84
(s, 1H), 4.95–4.92 (m, 1H), 4.54–4.50 (m, 1H), 3.02
(td, J = 11.2, 6.0 Hz, 1H), 2.84 (dd, J = 15.6, 5.6 Hz,
1H), 2.80–2.75 (m, 1H), 2.67–2.48 (m, 3H), 2.45 (s,
3H), 2.42 (s, 3H), 2.02-1.91 (m, 1H); 13C NMR (100
MHz, CDCl3): 173.33, 134.20, 133.13, 129.67, 126.79,
124.78, 119.93, 116.00, 108.67, 54.49, 37.78, 31.81,
25.99, 21.51, 21.29, 16.77; HRMS (ESI) : [M+H]+
Found 255.1509; Calculated 255.1497; for C16H19N2O.
2.4d 1,2,3,6,7,12b-Hexahydroindolo[2,3-a]quinolizin-
4(12H)-one (4d): 30 mg, 62% yield, off white solid;
M.p.: 239–240◦C, (Lit.19 240–241◦C); IR (KBr, cm−1):
1
3265, 3052, 1596, 1434, 1262; H NMR (400 MHz,
CDCl3): δ 7.85 (s, 1H), 7.51 (d, J = 7.6 Hz, 1H),
7.34 (d, J = 8.0 Hz, 1H), 7.21–7.16 (m, 1H), 7.15–
7.09 (m, 1H), 5.20–5.13 (m, 1H), 4.84–4.75 (m, 1H),
2.90–2.72 (m, 3H), 2.61–2.57 (m, 1H), 2.41 (m, 2H),
1.96–1.95 (m, 1H), 1.88–1.73 (m, 2H); 13C NMR (100
MHz, CDCl3): 169.24, 136.23, 133.32, 126.90, 122.15,
119.83, 118.41, 110.94, 109.59, 54.40, 40.16, 32.44,
29.07, 21.01, 19.40.
2.4a 7,8,13,13b-Tetrahydro-5H-benzo[1,2]indolizino
[8,7-b]indol-5-one (4a): 38 mg,69% yield, pale yellow
solid; M.p. 215–216◦C (Lit.16 212–214◦C); IR (KBr,
cm−1): 3225, 2932, 2841, 1670, 1461; 1H NMR
(400 MHz, CDCl3): δ 8.33 (s, 1H), 7.91 (d, J = 7.6 Hz,
1H), 7.81 (dd, J = 7.6, 1.0 Hz, 1H), 7.62 (td, J = 7.6, 2.4e 2,3,4,4a,7,8,13b,13c-Octahydro-1H-benzo[1,2]
1.0 Hz, 1H), 7.52–7.47 (m, 2H), 7.37 (d, J = 8.1 Hz, indolizino[8,7-b]indol-5(13H)-one (4e): 41 mg, 73%
1H), 7.22 – 7.16 (m, 1H), 7.11 (td, J = 7.6, 1.0 Hz, 1H), yield, pale yellow solid. M.p. 248–249◦C; IR (KBr,
5.83 (s, 1H), 4.87 (ddd, J = 13.0, 6.0, 0.7 Hz, 1H), 3.41 cm−1): 3294, 2928, 2846, 1668, 1429, 1346, 1273;
(ddd, J = 13.0, 11.0, 5.1 Hz, 1H), 2.98 (dddd, J = 13.8, 1H NMR (400 MHz, CDCl3): δ 8.00 (br s, 1H), 7.51
11.0, 6.1, 2.5 Hz, 1H), 2.92 – 2.84 (m, 1H); 13C-NMR (d, J = 7.6 Hz, 1H), 7.34 (d, J = 8.0 Hz, 1H), 7.18

815
(td, J = 6.8, 1.2 Hz, 1H), 7.15-7.11 (m, 1H), 4.86 (d, 1H), 4.54 (ddd, J = 12.8, 5.6, 1.2 Hz, 1H), 3.00–2.93
J = 5.2 Hz, 1H), 4.54 (dd, J = 12.8, 5.2 Hz, 1H), (m, 1H), 2.81–2.74 (m, 3H), 2.67–2.60 (m, 1H), 2.32
3.01-2.75 (m, 4H), 2.69–2.62 (m, 1H), 2.34–2.31 (m, (d, J = 14.4 Hz, 1H), 1.54–1.45 (m, 3H), 1.27–1.23
1H), 1.58–1.46 (m, 3H), 1.29–1.25 (m, 1H), 1.17–1.01 (m, 1H), 1.27–1.04 (m, 2H), 0.82–0.72 (m, 1H); 13C
(m, 2H), 0.83–0.73 (m, 1H); 13C-NMR (100 MHz, NMR (100 MHz, DMSO-d6): δ 172.65, 156.87 (d,
DMSO-d6): 172.46, 136.25, 131.13, 126.44, 120.88, J = 230.0 Hz, 1C), 133.44, 132.94, 126.76 (d, J =
118.46, 117.69, 111.00, 107.78, 55.59, 41.90, 37.03, 10.0 Hz, 1C), 111.90 (d, J = 10.0 Hz, 1C), 108.79 (d,
36.64, 23.42, 23.29, 22.58, 22.46, 20.80; HRMS (ESI) J = 26.0 Hz, 1C), 108.28 (d, J = 5.0 Hz, 1C), 102.73
(m/z) : [M+H]+ Found 281.1652; Calculated 281.1654; (d, J = 23.0 Hz, 1C), 55.68, 41.98, 37.06, 36.67,
for C18H21N2O.
23.49, 23.33, 22.61, 22.50, 20.82; HRMS-ESI (m/z):
[M+H]+ Found 299.1599 and calculated 299.1560 for
C18H20FN2O.
2.4f 12-Methyl-2,3,4,4a,7,8,13b,13c-octahydro-1H-
benzo[1,2]indolizino[8,7-b]indol-5(13H)-one (4f): 50 mg,
86% yield, pale yellow solid; M.p. 220–221◦C; FT-IR 2.4i 10-Chloro-2,3,4,4a,7,8,13b,13c-octahydro-1H-
(KBr, cm−1): 3287, 2928, 2852, 1673, 1434, 1302, benzo[1,2]indolizino[8,7-b]indol-5(13H)-one (4i): 47 mg,
1
1271; H NMR (400 MHz, CDCl3): δ 7.96 (s, 1H), 74% yield, brown solid; M.p. 250–251◦C; FT-IR (KBr,
7.36 (d, J = 8.0 Hz, 1H), 7.07-7.03 (m, 1H), 7.00 cm−1): 3254, 2932, 2848, 1668, 1428, 1268, 671; H
1
(d, J = 7.2 Hz, 1H), 4.88 (d, J = 4.9 Hz, 1H), 4.54 (dd, NMR (400 MHz, DMSO-d6): δ 11.24 (br s, 1H), 7.45
J = 12.8, 4.8 Hz, 1H), 3.01–2.92 (m, 1H), 2.90–2.75 (d, J = 2.0 Hz, 1H), 7.33 (dd, J = 8.4, 0.4 Hz, 1H),
(m, 3H), 2.71–2.64 (m, 1H), 2.50 (s, 3H), 2.34–2.30 7.04 (dd, J = 8.8, 2.4 Hz, 1H), 4.86 (d, J = 4.4Hz,
(m, 1H), 1.57–1.46 (m, 4H), 1.31–1.00 (m, 2H), 1H), 4.27 (dd, J = 12.8, 5.6 Hz, 1H), 2.90 (td, J =
0.83–0.73 (m, 1H); 13C NMR (100 MHz, CDCl3): 12.8, 4.4 Hz, 1H), 2.80 (dd, J = 15.2, 4.4 Hz, 1H),
δ 173.77, 135.93, 129.76, 126.41, 122.80, 120.06, 2.72–2.65 (m, 2H), 2.61–2.53 (m, 1H), 2.08–2.04 (m,
120.00, 116.02, 110.80, 56.42, 43.00, 38.12, 37.35, 1H), 1.48–1.40 (m, 3H), 1.17–1.11 (m, 1H), 1.07–0.97
29.69, 23.71, 23.04, 22.63, 21.21, 16.72; HRMS-ESI (m, 1H), 0.93–0.85 (m, 1H), 0.59–0.49 (m, 1H); 13C
(m/z): [M+H]+ Found 295.1809 and calculated NMR (100 MHz, DMSO-d6): δ 172.40, 134.67, 133.13,
295.1810 for C19H23N2O.
127.59, 123.17, 120.69, 117.07, 112.44, 107.84, 55.48,
41.84, 36.94, 36.48, 23.37, 23.24, 22.51, 22.40, 20.63;
HRMS-ESI (m/z): [M+H]+ Found 315.1263 and cal-
culated 315.1264 for C18H20ClN2O.
2.4g 10,12-Dimethyl-2,3,4,4a,7,8,13b,13c-octahydro-
1H-benzo[1,2]indolizino[8,7-b]indol-5(13H)-one (4g):
50 mg, 81% yield, pale yellow solid; M.p. 236–237◦C;
FT-IR (KBr, cm−1): 3251, 2937, 2846, 1668, 1430, 2.4j 10-Bromo-2,3,4,4a,7,8,13b,13c-octahydro-1H-
1
1365, 1269; H NMR (400 MHz, CDCl3): δ 7.68 (s, benzo[1,2]indolizino[8,7-b]indol-5(13H)-one (4j): 55 mg,
1H), 7.15 (s, 1H), 6.84 (s, 1H), 4.86 (d, J = 4.8 Hz, 77% yield, yellow solid; M.p. 253–254◦C; FT-IR (KBr,
1H), 4.55–4.45 (m, 1H), 2.99–2.91 (m, 1H), 2.83–2.74 cm−1): 3249, 2929, 2847, 1668, 1429, 1310, 1228,
(m, 3H), 2.69–2.61 (m, 1H), 2.45 (s, 3H), 2.42 (s, 796; 1H NMR (400 MHz, CDCl3): δ 8.60 (s, 1H), 7.62
3H), 2.33-2.30 (m, 1H), 1.54–1.45 (m, 3H), 1.27–1.23 (d, J = 2.0 Hz, 1H), 7.261–7.19 (m, 2H), 4.84 (d,
(m, 1H), 1.16–1.01 (m, 2H), 0.82–0.72 (m, 1H); 13C J = 4.8 Hz, 1H), 4.55 (dd, J = 4.8, 9.2 Hz, 1H), 3.00–
NMR (100 MHz, CDCl3): δ 173.85, 134.35, 130.07, 2.93 (m, 1H), 2.86–2.72 (m, 3H), 2.70–2.65 (m, 1H),
129.53, 126.81, 124.61, 119.86, 115.83, 110.51, 56.56, 2.32–2.29 (m, 1H), 1.54–1.46 (m, 3H), 1.28–1.25 (m,
43.14, 38.32, 37.48, 23.86, 23.80, 23.20, 22.78, 21.48, 1H), 1.11–1.00 (m, 2H), 0.80–0.70 (m, 1H); 13C NMR
21.36, 16.80; HRMS-ESI (m/z): [M+H]+ Found (100 MHz, DMSO-d6): δ 172.44, 134.93, 132.97,
309.1967 and calculated 309.1967 for C20H25N2O.
128.30, 123.27, 120.11, 112.97, 111.09, 107.78, 55.47,
41.86, 36.96, 36.50, 23.39, 23.26, 22.53, 22.42, 20.63;
HRMS-ESI (m/z): [M+H]+ Found 359.0760 and cal-
culated 359.0759 for C18H20BrN2O.
2.4h 10-Fluoro-2,3,4,4a,7,8,13b,13c-octahydro-1H-
benzo[1,2]indolizino[8,7-b]indol-5(13H)-one(4h): 45 mg,
76% yield, pale yellow; M.p. 263–264◦C; FT-IR (KBr,
cm−1): 3281, 2942, 2846, 1673, 1450, 1426, 1320, 2.4k 12-Fluoro-2,3,4,4a,7,8,13b,13c-octahydro-1H-
1
1251, 1225, 847; H NMR (400 MHz, CDCl3): δ 7.88 benzo[1,2]indolizino[8,7-b]indol-5(13H)-one(4k): 43 mg,
(s, 1H), 7.34-7.25 (m, 1H), 7.14 (dd, J = 9.0, 2.4 Hz, 72% yield, pale yellow solid; M.p. 280–281◦C; FT-IR
1H), 6.92 (td, J = 9.0, 2.4 Hz, 1H), 4.85 (d, J = 4.8 Hz, (KBr, cm−1): 3260, 2939, 2845, 1668, 1427, 1347,

816
Selvaraj Mangalaraj et al.
1
evaporation of the solvent hoping to get a single crystal
of the intermediate. Fortunately, the CDCl3 solution of
2a+BBr3 furnished the cubic orange red colour crystals
suitable for crystal structure analysis. The presence of
fusedcyclicN-acyliminiumionas an intermediate along
with counter anion Br−3 was obtained by X-ray crys-
tallographic analysis (figure 2). Since, the mixture
2a+BBr3 had been stored for long period of time, the
decomposition of excess BBr3 might have produced
Br2. The reaction of Br2 with Br− might have gener-
ated Br−3 as counter anion along with the fused cyclic
N-acyliminium ion.
1222, 732; H NMR (400 MHz, DMSO-d6): δ 11.47
(br, s, 1H), 7.23 (d, J = 7.6Hz, 1H), 6.97–6.93 (m, 1H),
6.92–6.87 (m, 1H), 4.86 (d, J = 3.2 Hz, 1H), 4.29 (dd,
J = 12.4, 5.6 Hz, 1H), 2.91 (td, J = 12.4, 4.0 Hz, 1H),
2.82 (dd, J = 15.2, 4.0 Hz, 1H), 2.78–2.73 (m, 2H),
2.64–2.56 (m, 1H), 2.08–2.05 (m, 1H), 1.47–1.43 (m,
3H), 1.18–1.15 (m, 1H), 1.08–0.98 (m, 1H), 0.93–0.83
(m, 1H), 0.60–0.50 (m, 1H); 13C NMR (100 MHz,
DMSO-d6): δ 172.49, 149.27 (d, J = 289.0 Hz, 1C),
132.50, 130.43, 123.72 (d, J = 12.0 Hz, 1C), 118.90,
113.99, 108.97, 105.96 (d, J = 17.0 Hz, 1C), 55.58,
41.83, 36.92, 36.50, 23.41, 23.28, 22.55, 22.44, 20.91;
HRMS-ESI (m/z): [M+Na]+ Found 321.1378 and
calculated 321.1379 for C18H19FN2ONa.
3.2 Synthesis of fused tetrahydro-β-carboline
derivatives
The successful intramolecular electrophilic substitu-
tion between aryl nucleophile and activated carbonyl
electrophile leads to the condensed heterocyclic lac-
tams from phenethylimides as well as indolyl ethyl
3. Results and Discussion
3.1 Structural characterization of the intermediate
The reaction of appropriately substituted phenethylph- imides.12 This encouraged us to extend the Lewis
thalimide 1a in presence of BBr3 successfully deliv- acid BBr3 assisted intramolecular cyclization method-
ered a dark red coloured cyclic compound which ology to other nucleophiles such as heteroarenes, which
after quenching with water furnished the isoindoloiso- are, eventually useful precursor to synthesize fused
quinolinone derivative 2a. The observation of dark red heteroarene polycyclic lactams. Indole, a heteroarene
coloured reaction mixture in this reaction indicates motif present in various physiologically active mole-
the formation of highly conjugated system as an inter- cules possesses the tendency to react with electrophiles
mediate.20 This was conveniently proved by analyzing very fast due to its electron rich nature.21 Hence, to
the1H NMRof the mixture of imide 1a and BBr3 as well increase the scope of this cyclization methodology, the
asthe mixture of cyclized compound 2a and BBr3 which indole nucleophile was chosen to replace the phenyl
were found super imposable with each other. Hence, nucleophile. To explore the reactivity of indole moiety
we speculated that the involvement of fused cyclic N- under this cyclization condition (using BBr3) various
1
acyliminium ion I as an intermediate. The H NMR substituted and unsubstituted indolylethylimides imides
study showed that the cyclized product 2a and starting are prepared. The unsubstituted indolylethylimides are
material 1a on treatment with BBr3 afforded the same prepared by simple condensation reaction of tryptamine
compound, the fused cyclic N-acyliminium ion I, which with corresponding anhydrides (figure 3).12d
on quenching with water furnished the hydroxy lactam
The required substituted indolylethylimides are
2a. To further ascertain and prove the 1H NMR spectro- conveniently prepared in four simple steps adopting
scopic evidence for the involvement of fused cyclic N- the methodology developed in this laboratory.12d,17
acyliminium ion, we have initiated our effort to get the This involves the condensation of anhydride with 4-
single crystal suitable for structural analysis (scheme 1). aminobutanol followed by Swern oxidation of primary
Hence, the CDCl3 solutions of 1a+BBr3 and alcohol to aldehyde. The aldehyde was protected in situ
2a+BBr3 in two NMR tubes were left aside for slow using 1,3-propanediol in presence of catalytic amount
Scheme 1. Generation of fused cyclic N-acyliminium ion.

817
of p-toluenesulphonic acid. Finally, the imide deriva- intermediate, instead of quenching with water, using
tives of tryptamine were successfully arrived at through NaBH4/TFA mixture was carried out to avoid the
the Fischer indole synthesis protocol from protected formation of hydroxyl lactam. This cyclization and
aldehyde and substituted phenylhydrazine hydrochlo- reduction sequence successfully furnished the con-
ride in good yields (table 1). Imide 4c is prepared by densed pentacyclic tetrahydro-β-carboline 4a in 69%
following our earlier reported procedure from succinic yield. Success of this experiment prompted us to
anhydride and dimethylpheneylhydrazine hydrochlo- examine the other substituted indolylethylimide deriva-
ride (table 1).12d
tives. As expected all the imides under one-pot
Indolylethylphthalimide similar to phenethylphthal- cyclization and reduction sequence delivered the
imide is expected to deliver fused cyclic N-acyliminium cyclized products in good yields. For complete con-
ion under established cyclization condition with BBr3. version of imides to fused cyclic iminium ion, the
Accordingly, the phthalimide derivative of tryptamine unsubstituted and methyl substituted indolylethylim-
3a was treated with BBr3 in dichloromethane at 0◦C to ides required 12 h at room temperature in pres-
room temperature and that delivered the fused cyclic ence of BBr3 (5 equiv) (table 2). On the other
N-acyl iminium ion. In situ reduction of iminium ion hand, substituted indolylethylimides 4e–4k required 24 h
Figure 2. ORTEP diagram of the fused cyclic N-acyliminium ion with 50% probability level.
3a
3b
3d
3e
Figure 3. Unsubstitued indolylethylimides prepared to synthesize THBC’s.
Table 1. Preparation of substituted 2-(3-indolyl)ethylimides.

818
Selvaraj Mangalaraj et al.
Table 2. Synthesis of fused THBC polycyclic lactams.
at room temperature in presence of BBr3 (10 equiv) 4. Conclusions
(table 2).
We have established a simple and convenient method-
The inductively electron withdrawing groups such
as fluoro, chloro and bromo substituents present in the
indole moiety reduces the nucleophilicity of indole ring
and that might have been the reason for increase in
reaction time. Fused cyclic N-acyliminium ions gener-
ated from the imides 3e–k underwent diastereoselec-
tive reduction using NaBH4/MeOH and produced single
diastereomer of the cyclized compounds 4e–k. From
1H NMR spectra of the cyclized molecules the rela-
tive orientation of the hydrogen attached with ring junc-
tion carbons are found to be cis orientated.12d Plenty
of indole alkaloids contain fused polyalicyclic ring sys-
tems with THBC units. Hence, this methodology would
be an easy protocol to synthesize diverse alicyclic units
fused with THBC cores.
ology for the synthesis of condensed THBC poly-
cyclic lactamic skeletons from the corresponding easily
accessible imides, through Lewis acid activation of
imide carbonyl group. The formation of fused cyclic
N-acyliminium ion in this cyclization reaction was
supported by single crystal X-ray structural analysis.
Supplementary Information
CCDC details for the iminium ion (932118), 1H and 13C
NMR spectra of the imides 3f-3k and all cyclized com-
pounds 4a–4k are provided in Supporting information
which is available at www.ias.ac.in/chemsci.

819
129 13404
Acknowledgements
7. Smith M W, Hunter R, Patten D J and Hinz W 2009
Tetrahedron Lett. 50 6342
We thank CSIR and DST for financial support. J. S.
thanks CSIR (New Delhi) for SRF. S.M.R thanks UGC
(New Delhi) for SRF. We gratefully acknowledge CIF,
Pondicherry University for NMR/IR data and DST-
FIST sponsored Single crystal XRD facility and HRMS
facility, Department of Chemistry.
8. Liu L and Zhang L 2012 Angew. Chem. Int. Ed. 51 7301
9. (a) Openshaw H W and Whittaker N 1963 J. Chem.
Soc. 1449; (b) Itoh T, Yokoya M, Miyauchi K, Nagata
K and Ohsawa A 2003 Org. Lett. 5 4301; (b) Itoh T,
Yokoya M, Miyauchi K, Nagata K and Ohsawa A 2006
Org. Lett. 8 1533; (c) Nagata K, Ishikawa H, Tanaka H,
Miyazaki M, Kanemitsu T and Itoh T 2010 Heterocycles
81 1791; (d) Lalonde M P, McGowan M A, Rajapaksa
N S and Jacobsen E N 2013 J. Am. Chem. Soc. 135
1891
References
10. (a) Stearman C J, Wilson M and Padwa A 2009 J. Org.
Chem. 74 3491; (b) Poissonnet G, Theret-Bettiol M H
and Dodd R H 1996 J. Org. Chem. 61 2273
11. (a) Ma J, Yin W, Zhou H, Liao X and Cook J M 2009
J. Org. Chem. 74 264; (b) Zhang C, Das D and Seidel D
2011 Chem. Sci. 2 233; (c) Yu F, Cheng B and Zhai H
2011 Org. Lett. 13 5782
12. (a) Selvakumar J, Makriyannis A and Ramanathan C R
2010 Org. Biomol. Chem. 8 4056; (b) Selvakumar J and
Ramanathan C R 2011 Org. Biomol. Chem. 9 7643; (c)
Harikrishnan A, Selvakumar J, Gnanamani E, Suman B
and Ramanathan C R 2013 New J. Chem. 37 563; (d)
Mangalaraj S and Ramanathan C R 2012 RSC Adv. 2
12665
13. (a) Yazici A and Pyne S G 2009 Synthesis 339; (b) Yazici
A and Pyne S G 2009 Synthesis 513; (c) Maryanoff B E,
Zhang H C, Cohen J H, Turchi I J and Maryanoff C A
2004 Chem. Rev. 104 1431
14. Science of Synthesis Volume 27 2004 A Padwa (Ed.)
(Germany: George Thieme Verlag) p. 375
1. Wehner F, Noren-Muller A, Müller O, Reis-Correa Jr. I,
Giannis A and Waldmann H 2008 Chem. Bio Chem. 9
401; (b) Takayama H, Ishikawa H, Kurihara M, Kitajima
M, Aimi N, Ponglux D, Koyama F, Matsumoto K,
Moriyama T, Yamamoto L T, Watanabe K, Murayama T
and Horie S J 2002 J. Med. Chem. 45 1949; (c) Cook P
and James I N 1981 Engl. J. Med. 305 1560; (d) Santos
L S, Theoduloz C, Pilli R A and Rodriguez J 2009 Eur.
J. Med. Chem. 44 3810; (e) Kochanowska-Karamyan
A J and Hamann M T 2010 Chem. Rev. 110 4489; (f)
Cox E D and Cook J M 1995 Chem. Rev. 95 1797; (g)
Somei M and Yamada F 2004 Nat. Prod. Rep. 21 278;
(h) Kawasaki T and Higuchi K 2005 Nat. Prod. Rep. 22
761; (i) O’Connor S E and Maresh J J 2006 Nat. Prod.
Rep. 23 532; (j) Shen Y-C, Chen C-Y, Hsieh P-W, Duh
C-Y, Lin Y-M and Ko C-L 2005 Chem. Pharm. Bull.
53 32
2. (a) Dieters A, Petterson M and Martin S F 2006 J. Org.
Chem. 71 6547; (b) Takasu K, Nishida N, Tomimura A
and Ihara M 2005 J. Org. Chem. 70 3957; (c) Amat A,
Gómez-Esqué A, Escolano C, Santos M M M, Molins E
and Bosch J 2009 J. Org. Chem. 74 1205
15. Liu Y, Luo S, Fu X, Fang F, Zhuang Z, Xiong W, Jia X
and Zhai H 2006 Org. Lett. 8 115
16. Hoefgen B, Decker M, Mohr P, Schramm A M,
Rostom S A F, Subbagh H E, Schweikert P M, Rudolf
D R, Kassack M U and Lehmann J 2006 J. Med. Chem.
49 760
17. Chen C, Senanayake C H, Bill T J, Larsen R D,
Verhoeven T R and Reider P J 1994 J. Org. Chem. 59
3738
3. (a) Holloway C A, Muratore M E, Storer R I and Dixon
D J 2010 Org. Lett. 12 4720; (b) Mondal P and Argade
N P 2013 J. Org. Chem. 78 6802
4. Cai Q, Liang X-W, Wang S-G, Zhang J-W, Zhang X and
You S-L 2012 Org. Lett. 14 5022
5. Wu X, Dai X, Fang H, Nie L, Chen J, Cao W and Zhao
G 2011 Chem. Eur. J. 17 10510
18. da Silva W A, Rodrigues Jr M T, Shankaraiah N,
Ferreira R B, Andrade C K Z, Pilli R A and Santos L S
2009 Org. Lett. 11 3238
19. Airiau E, Girard N, Mann A, Salvadori J and Taddei M
2009 Org. Lett. 11 5314
20. Osantae I, Lete E and Sotomayor N 2004 Tetrahedron
Lett. 45 1253
21. Lakhdar S, Westermaier M, Terrier F, Goumont R,
Boubaker T, Ofial A R and Mayr H 2006 J. Org. Chem.
71 9088
6. (a) Nuhant P, Raikar S B, Wypych J C, Delpech B
and Marazano C 2009 J. Org. Chem. 74 9413;
(b) Komnatnyy V V, Givskov M and Nielsen T E 2012
Chem. Eur. J. 18 16793; (d) Wawzonek S and Nordstorm
J D 1960 J. Am. Chem. Soc. 82 5941; (c) Lebold T P,
Wood J L, Deitch J, Lodewyk M L, Tantillo D J and
Sarpong R 2013 Nat. Chem. 2013 5 126; (d) Chiou W
H, Lin G H, Hsu C C, Chaterpaul S J and Ojima I
2009 Org. Lett. 11 2659; (e) Raheem I T, Thiara P S,
Peterson E A and Jacobsen E N 2007 J. Am. Chem. Soc.