Triflic Acid Mediated Cyclization of Unsymmetrical N -Phenethyl- and N -(3-Indolylethyl)succinimides: Regio- and Diastereoselective Synthesis of Substituted Pyrroloisoquinolinones and Indolizino-indolones

Article abstract of DOI:10.1055/s-0036-1588639

The regio and diastereoselective synthesis of 1 or 2 alkyl-substituted pyrroloisoquinolinones and indolizinoindolones by triflic acid mediated cyclization via an electrophilic activation of unsymmetrical succinimide carbonyl groups followed by the reducti

Full text of DOI:10.1055/s-0036-1588639

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2016, 48, A–L
paper
A
J. Selvakumar et al.
Paper
Synthesis
Triflic Acid Mediated Cyclization of Unsymmetrical N-Phenethyl-
and N-(3-Indolylethyl)succinimides: Regio- and Diastereoselective
Synthesis of Substituted Pyrroloisoquinolinones and Indolizino-
indolones
Jayaraman Selvakumar
O
Selvaraj Mangalaraj
Ar
Ar
1. TfOH
R
N
N
Kamsali Murali Mohan Achari
Krishna Mukund
+
N
O
O
2. NaBH4
Ar
O
R
phenyl
Chinnasamy Ramaraj Ramanathan*
R
minor
major
equal
major
R1-indole
minor
Ar = phenyl or indole
R2-indole
equal
Department of Chemistry, Pondicherry University,
Puducherry 605 014, India
crrnath.che@pondiuni.edu.in
R1 = H, F, Br; R2 = Me, OMe
14 examples
Received: 30.08.2016
Accepted after revision: 08.10.2016
Published online: 24.11.2016
trophilic activation of imide carbonyl group8 towards the
synthesis of fused tetrahydroisoquinoline, tetrahydro-β-
carboline derivatives, and related simple alkaloids prompt-
ed us to extend this methodology for the synthesis of more
functionalized alkaloid classes by examining the stereo-
chemical outcome of cyclization/reduction strategy with
unsymmetrically substituted succinimides. The outcome of
this study by subjecting the unsymmetrical succinimides
under Brønsted acid mediated cyclization condition may
throw a light on the possibility of using this methodology
to synthesize some complex alkaloid molecules.
DOI: 10.1055/s-0036-1588639; Art ID: ss-2016-t0597-op
Abstract The regio and diastereoselective synthesis of 1 or 2 alkyl-
substituted pyrroloisoquinolinones and indolizinoindolones by triflic
acid mediated cyclization via an electrophilic activation of unsymmetri-
cal succinimide carbonyl groups followed by the reduction of fused cy-
clic N-acyliminium ion is reported. This strategy successfully furnished
the pyrroloisoquinolinone and indolizinoindolone derivatives in regio-
and diastereoselective manner. The steric factor dictates the regiose-
lectivity in N-phenethyl unsymmetrical succinimides and electronic fac-
tor seems to dictate the regioselectivity in N-(3-indolylethyl) unsym-
metrical succinimides.
MeO
HO
Key words triflic acid, regioselectivity, diastereoselectivity, pyrrolo-
isoquinolinones, indolizinoindolones
N
N
N
MeO
HO
O
N
H
Crispine A
Trolline
Harmicine
Pyrroloisoquinoline and indoloindolizine class of mole-
cules, respectively, belong to the pharmacologically import-
ant tetrahydroisoquinoline and tetrahydro-β-carboline al-
kaloid families.1 The alkaloids crispine A, trolline, harmi-
cine, erysotramidine, subincanadine B, and tacamonine, for
example, possesses either tetrahydroisoquinoline or tetra-
hydro-β-carboline skeletons (Figure 1).2 The simple pyr-
roloisoquinoline3 and indoloindolizine4 alkaloids can be
easily accessed from simple substrates. On the other hand
the substituted/functionalized alkaloids, for example, erys-
otramidine5 and tacamonine6 are synthesized by either
functionalizing the basic core or assembling the target mol-
ecules with regio/chemoselective manner. Several types of
reactions7 have been utilized to construct the isoquinoline
units including Bischler–Napieralski reaction. Our continu-
ous exploration of Lewis acid/Brønsted acid mediated elec-
MeO
MeO
H
H
N
N
N
O
N
N
Me
H
MeO
O
HO
H
Erysotramidine
( )-Tacamonine
Subincanadine B
Figure 1 Simple and functionalized pyrroloisoquinoline and indoloin-
dolizine alkaloids
Introduction of substituent at α-carbon of the succinim-
ide unit leads to nonidentical carbonyl groups. Unsymmet-
rical succinimide under Brønsted acid assisted cyclization
may potentially give rise to two regioisomeric mixture of
fused cyclic N-acyliminium ions, a prochiral substrate,
which on reduction using NaBH4/MeOH mixture may gen-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

B
J. Selvakumar et al.
Paper
Synthesis
erate a diastereomeric mixture of products due to the pres-
ence of an additional chiral center present in the imide por-
tion (Figure 2). The α-methyl-substituted succinimide 1a
was chosen as a model substrate for this study. The succin-
imide 1a was prepared in two steps from the corresponding
N-phenethylmaleimide.9 This N-phenethyl unsymmetrical
succinimide was subjected to TfOH-mediated cyclization at
0 °C in dichloromethane. After the consumption of imide
(monitored by TLC), the generated fused cyclic N-acylimini-
um ion was reduced with NaBH4 in methanol at room tem-
perature. The crude reaction mixture revealed the pres-
ence of two regioisomeric products in 65:35 ratio. These
two regioisomers were successfully separated by column
chromatography. The less sterically crowded isomer 2aa
was obtained in 58% yield while the sterically crowded re-
gioisomer 2ab was produced in 31% yield (Scheme 1). Inter-
estingly, a complete diastereoselectivity was observed in
this cyclization and reduction sequences. Out of two possi-
ble diastereomers (cis and trans relation between C10bH
and CH3 group) only the trans-diastereomer of each regio-
isomer was produced as evidenced from the 2D NOESY ex-
periment. Based on the correlation observed between the
hydrogen on C10b with the hydrogen on either C2 of 2-
methyl isomer 2aa or with the hydrogen on C1 of 1-methyl
isomer 2ab, the hydrogen on C10b is trans to either C1 or
C2 substituents (cis to the C1 proton and C2 proton). To ex-
amine more about this regio- and diastereoselective out-
come various unsymmetrical succinimides 1b–h with dif-
ferent substitutions (propyl, benzyl, and benzilidine) were
prepared and subjected to cyclization and reduction se-
quences (Table 1).
purely dependent on the steric factor. As the steric crowd
increases, the yield of 2-isomer is also increased (imide 1b,
Table 1). In certain cases with much bulkier substituents
such as 3-methoxybenzyl and 3,5-dimethoxybenzyl
groups, the imides exclusively produced the 2-alkyl-substi-
tuted pyrroloisoquinolinones (imides 1c, and 1f–h, Table 1).
2D-NMR study of these molecules also proved the existence
of trans geometry between the hydrogen on C10b and
C1/C2 substituents. These observations clearly indicate that
the transfer of hydride occurred through the α-face as
shown in Figure 2.
The erythrina alkaloids possess additional ring system
fused at C10b and C1 position. These fused systems may po-
tentially be derived from 1-substituted pyrroloisoquinoli-
none. Unfortunately, the unsymmetrical succinimides un-
der present condition delivered both regioisomers with 1-
substituted derivatives as the minor product and 2-substi-
tuted derivatives as the major component. It was assumed
that the lowering of reaction temperature may alter the re-
gioselectivity towards 1-substituted derivative. Hence, the
reactions were conducted at room temperature, 0 °C, –40
1
°C, and –78 °C with imide 1a (Table 2). The crude H NMR
spectra of the reaction mixture of these experiments re-
vealed that the lowering of reaction temperature did not al-
ter the regioisomeric ratio significantly. Surprisingly, the
reaction of imide 1e at –40 °C gave a regioisomeric ratio of
63:37 containing 37% of 1-methylpyrroloisoquinolinone;
however, the same imide 1e gave a regioisomeric ratio of
74:26 with only 26% of the 1-methyl isomer when the reac-
tion was performed at 0 °C (Table 2). The benzyl-substitut-
ed imides 1c and 1f gave only 2-benzylpyrroloisoquinoli-
nones when the reaction was performed at –40 °C. The
temperature effect on the unsymmetrical succinimides fur-
ther confirms that the regioselectivity and diastereoselec-
tivity of these imides depend mainly on steric factor.
regioselectivity
diastereoselectivity
b
b
O
Nu
a
N+
hydride
transfer
N
O
O
To extend this regioselective cyclization followed by di-
astereoselective reduction methodology to synthesize sub-
stituted β-carboline derivatives, various α-benzylated N-(3-
indolylethyl)succinimides 3a–g were prepared10 and sub-
jected to TfOH-mediated cyclization condition (Table 3).
Since, all the benzyl-substituted N-phenethylsuccinimides
delivered single regio- and diastereomers, it was speculated
that the benzyl-substituted N-(3-indolylethyl)succinimide
3a under standard cyclization/reduction condition would
also deliver single regio- and diastereomer. In contrast to
our speculation, the imide 3a under cyclization followed by
reduction condition delivered two regioisomers. Chromato-
α
β
Vs
R
O
N+
a
C–C bond formation
Nu = phenyl or indole
Figure 2 The regioselective cyclization and diastereoselective reduc-
tion of unsymmetrical succinimides
Formation of 2-alkyl-substituted pyrroloisoquinolinone
derivatives (from imides 1a,b and 1d–e, Table 1) as major
product was witnessed and that accounts for the re-
giochemical outcome of this cyclization reaction, which is
O
MeO
MeO
1. TfOH (4 equiv), CH2Cl2,
MeO
MeO
N
N
C10b
0 °C to rt, 3 h
N
O
MeO
+
O
MeO
2ab, 31%
C10b
H
O
2. NaBH4, MeOH, 15 min
H
2
1
1a
2aa, 58%
Scheme 1 Regioselective cyclization and diastereoselective reduction of 1a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

C
J. Selvakumar et al.
Paper
Synthesis
graphic separation of regioisomers by column chromatog-
raphy on neutral alumina using ethyl acetate and hexane as
eluents afforded the sterically hindered isomer 4ab in 55%
yield and sterically less hindered isomer 4aa in 26% yield.
The 2D NOESY analysis of the two regioisomers 4aa and
4ab revealed the correlation between the hydrogens of
C11b and C1 of 1-benzyl isomer 4ab and the correlation be-
tween the hydrogens of C11b and C2 of 2-benzyl isomer
4aa confirmed the transfer of hydride occurred trans to the
substituents face. Unsubstituted and halogen-substituted
unsymmetrical succinimide derivatives of tryptamines
upon treatment with TfOH produced the sterically hin-
dered product in major quantity and steric-free product in
minor quantity (from imides 3a, 3b, 3c, and 3g Table 3). But
the unsymmetrical succinimide derivatives of electron-
donating group-substituted tryptamines produced two re-
gioisomeric products in nearly equal ratio (3d, 3e, and 3f,
Table 3). The existence of trans geometry between the hy-
drogen on C11b and C1/C2 substituents was proven in the
2D-NMR study of these molecules and thus the diastereose-
Table 1 Effect of Substitution on Regio- and Diastereoselective Cyclization of Unsymmetrical N-Phenethyl Succinimidesa
Entry
Substrate
Time (h)
Ratio
Regioisomer, yieldb
MeO
MeO
MeO
O
N
N
MeO
MeO
O
O
O
MeO
N
1
3
81:19
H
H
O
O
1b
2ba, 73%
2bb, 14%
MeO
MeO
O
N
R
MeO
MeO
N
2
2
100:0
H
OMe
1c
2ca, 83%
R = 3,5-(MeO)2C6H3CH2
OMe
MeO
O
MeO
N
MeO
N
N
O
3
4
2
1
77:23
74:26
O
H
OMe
H
OMe
O
1d
2da, 71%
2db, 16%
MeO
OMe
O
MeO
MeO
N
N
N
MeO
MeO
N
O
O
O
H
H
O
O
2eb, 14%
2ea, 63%
1e
O
R
N
5
6
1
1
100:0
100:0
H
OMe
1f
2fa, 56%
R = 3-MeOC6H4CH2
MeO
O
N
R
MeO
N
O
H
OMe
OMe
O
1g
2ga, 78%
R = 3,5-(MeO)2C6H3CH2
MeO
O
N
R
MeO
N
O
7
1
100:0
OMe
OMe
O
1h
2ha, 60%
R = 3,5-(MeO)2C6H3CH=
a Reaction conditions: imide 1b–h (0.5 mmol), CH2Cl2 (10 mL), TfOH (2 mmol), 0 °C to r.t.
b Yield of isolated product.
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D
J. Selvakumar et al.
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Table 2 Effect of Temperature on Regio- and Diastereoselectivity
O
MeO
R
MeO
R
1. TfOH (4 equiv), CH2Cl2
MeO
R
N
N
0 °C to rt
N
O
+
O
H
O
2. NaBH4, MeOH, 15 min
H
1a: R = OMe
1e: R = H
2aa, 2ea
2ab, 2eb
Regioisomeric ratio
2aa/2ab
Regioisomeric ratio
2ea/2eb
r.t.
0 °C
65:35
–40 °C
64:36
–78 °C
62:38
0 °C
–40 °C
63:37
67:33
74:26
lectivity during the hydride transfer step. The regioselectiv-
ity observed is quite interesting as this cyclization reduc-
tion sequence reaction may be applied to synthesize the ta-
camonine type of alkaloids. Single-crystal X-ray analysis of
4ba support the relative orientation between C10b hydro-
gen and C2 methyl carbon is trans (Figure 3).11 The reason
for difference in the regioselectivity of phenyl and indole
nucleophile may be explained through the possible involve-
ment of cation–π interaction between indole nitrogen and
phenyl substituents on the imide moiety during the reac-
tion (Figure 4, a).12
The net positive charge on the nitrogen may be dimin-
ished when electron-donating groups are present on the in-
dole moiety (methoxy and methyl) while this reduction in
positive charge affects the magnitude of the cation–π inter-
action. Hence, the sterically crowded and less crowded iso-
mers were formed in equal amounts. Such interaction is not
possible with the imides 1a–h and therefore sterics influ-
ence the regioselectivity.
N-Acyliminium ion cyclization is a well explored meth-
odology for the construction of simple fused tetrahydroiso-
quinolines and tetrahydro-β-carbolines, but was not ex-
plored on the regioselective and diastereoselective cycliza-
tion of the unsymmetrical lactams. It is well recorded in the
literature that the unsymmetrical succinimides are known
to undergo regioselective partial reduction with NaBH4 in
methanol. It is obvious that such regioisomeric hydroxy lac-
tams produce corresponding cyclized products in the pres-
ence of Brønsted acid. To understand the stereochemical
outcome of the cyclization of the hydroxy lactam and to
compare this result with direct cyclization of unsymmetri-
cal succinimides, we carried out the cyclization of the par-
tially reduced imide 1b with trifluoroacetic acid (Scheme
2).13 The less crowded isomer was formed in 31% yield and
the crowded isomer was formed in 20% yield. The origin of
the regioselectivity of this reaction is determined by the re-
gioselective outcome of the partial reduction of imide car-
bonyl group, which is consistent with the earlier observa-
tion. The 1H and 2D NOESY NMR analysis of the product re-
veals that the less crowded product is not a single
diastereomer, rather a mixture of diastereomeres (cis and
trans 2ba + 2ba′ = 33:67) generated from N-acyliminium
ion. The crowded isomer 2bb′ was isolated as a single dia-
stereoisomer, which is completely cis (cis-diastereomer
with respect to C10bH and n-propyl group). The absence of
a cross peak between C10bH and C2H in 2D NOESY further
confirms the nature of the product 2bb′.
The TfOH-mediated cyclization of unsymmetrical suc-
cinimide followed by reduction of the mixture of fused cy-
clic N-acyliminium ions produced the single diastereomer
of sterically crowded 2bb and less crowded 2ba isomers.
Since the fused cyclic N-acyliminium ion is a rigid struc-
ture, the incoming hydride species approaches the imine
bond from the less hindered side (Figure 4, b). In the case of
partial reduction followed by cyclization, the generated N-
O
a)
b)
O
O
N
N
R
R
N
H–
H–
hydride approaches
from less hindered side
O
N
H
c)
O
O
N
N
cation-π interaction
for regioselectivity
R
R
nucleophile approaches
from both sides
nucleophile approaches
from less hindered side
Figure 3 ORTEP diagrams for the compound 4ba with 50% probability
level
Figure 4 Schematic explanation for regio- and diastereoselectivity
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

E
J. Selvakumar et al.
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Synthesis
Table 3 Regioselective Cyclization and Diastereoselective Reduction of N-(3-Indolylethyl) Unsymmetrical Succinimidesa
O
N
1. TfOH (10 equiv), 4 Å MS
CH2Cl2 rt, 12 h
O
O
N
N
O
R
N
H
R
R
N
H
N
H
2. NaBH4, MeOH, rt, 0.5 h
R'
R'
O
3a–g
R'
4(a–g)a
4(a–g)b
Entry
1
Succinimide
Regioisomer, yieldb
O
O
N
N
N
O
N
N
H
N
H
H
H
H
H
H
3a
Ph
4aa, 26%
4ab, 55%
Ph
Ph
N
F
F
F
O
O
N
O
N
2
N
H
O
N
H
N
H
H
3b
Ph
4ba, 23%
4bb, 54%
Ph
Ph
N
Br
Br
Br
O
O
O
N
N
3
4
5
N
H
O
Ph
N
H
N
H
H
3c
Ph
4ca, 21%
4cb, 50%
Ph
N
O
O
O
N
N
N
O
N
N
H
H
H
H
H
H
3d
Ph
Ph
4da, 37%
4db, 34%
Ph
N
O
O
O
N
N
N
H
O
N
H
N
H
H
3e
Ph
Ph
N
4ea, 37%
4eb, 39%
Ph
N
MeO
MeO
MeO
O
O
O
N
6
7
N
H
O
N
N
H
H
H
H
3f
Ph
4fa, 37%
Ph
Ph
4fb, 35%
Ph
N
O
O
O
N
N
N
O
N
H
N
H
H
H
Ph
4gb, 63%
H
Ph
Ph
3g
Ph
Ph
4ga, 23%
a Reaction conditions: imide 3a–g (0.7 mmol), CH2Cl2 (10 mL), TfOH (7 mmol), 0 °C to r.t.
b Yield of isolated product.
acyliminium ion is linear in structure and the incoming aryl
Based on this observation a plausible mechanism for re-
nucleophile approaches either from less hindered side to
the imine double bond to produce sterically crowded prod-
uct 2bb′ and a mixture of syn- and anti-addition produces
the less crowded product 2ba + 2ba′ (Figure 4, c).
gioselective cyclization and distereoslective reduction is
proposed (Scheme 3). The reaction may be initiated by pro-
tonation of the imide carbonyl group by TfOH followed by
the intramolecular nucleophilic (aryl or heteroaryl) addi-
tion and leads to the formation of fused cyclic N-acylimini-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

F
J. Selvakumar et al.
Paper
Synthesis
O
N
MeO
MeO
MeO
MeO
1. NaBH4, MeOH
0 °C to rt, 3 h
MeO
MeO
N
C10b
N
O
+
O
C10b
H
H
O
2. TFA, CH2Cl2
0 °C to rt, 3 h
2
1
1b
2ba + 2ba' (33:67), 31%
2bb', 20%
Scheme 2 N-Acyliminium ion cyclization of imide 1b
Ar
tions are unambiguously confirmed by NMR and single
crystal X-ray analysis. The switch over in the regioselectivi-
ty of the products from aryl to indole was observed for the
first time. The regio- and diastereoselectivity of this cy-
clization reaction also compared with the N-acyliminium
ion cyclization reaction. Further exploration of this meth-
odology to the α-substituted N-phenethyl- and N-(3-indo-
lylethyl)glutarimides and application to synthesize related
alkaloids are in progress.
Ar
N
N
O
O
O
O
R
R
TfOH
N+
TfOH
N+
O
O
A
R
R
B
R
R
Melting points were measured with Buchi M-560 (Buchi, Switzer-
land) melting point apparatus. IR spectra (in cm–1) were recorded on a
Thermo Nicolet 6700 FT-IR spectrophotometer by using KBr thin
films. HRMS data were measured by micromass Q-TOF (ESI-HRMS)
and Agilent-6530 B Q-TOF (ESI-HRMS). The 1H and 13C NMR spectro-
scopic data were recorded on a Bruker Avance 400 spectrometer. All
NMR spectra were recorded at r.t., either in CDCl3 or DMSO-d6 as sol-
vent with TMS as an internal standard. The chemical shifts are ex-
pressed in δ (ppm) downfield from the signal of the TMS. Coupling
constant (J-values) are given in hertz. Standard abbreviations are used
to report the multiplicities of the NMR signals. X-ray crystal data
were collected on an Oxford Diffraction Xcalibur diffractometer with
Mo-Kα radiation (λ = 0.71073 Å). The empirical absorption correction
by using spherical harmonics, implemented in SCALE3 ABSPACK scal-
ing algorithm, was applied. The structure solution and refinement
were performed with SHELX-97.14 All solvents that were used for the
reactions were distilled according to standard procedures.15 Anhyd
CH2Cl2 was obtained by distillation over CaH2. The substituted
phenethylamines were prepared from the corresponding aldehydes
by three simple synthetic steps that involved a nitroaldol condensa-
tion and a reduction of the double bond followed by nitro group re-
duction.16 The reagents TfOH, phenethylamine, and 3,4-dimethoxy-
phenethylamine from Aldrich were used without further purification.
Column chromatography was performed on Merck silica gel (100–
200 mesh). The developed TLC plates (Merck 60 F 254 precoated silica
plates) were visualized by using phosphomolybdic acid stain, KMnO4
stain, or UV light.
O
N+
O
N
R
H
B–
Na+
H
B–
Na+
hydride approaches
from less hindered
side
H
H
H
H
H
H
R
N
O
O
N
H
N
H
R
R
10b
10b
O
O
N
H
H
b isomer
a isomer
Scheme 3 Mechanism for triflic acid mediated regio- and diasterose-
lective synthesis of tetrrahydroisoquinolines and tetrahydro-β-carbo-
lines
um ions. Due to the existence of nonidentical carbonyl
groups on imides, the cyclization generated two regioiso-
meric N-acyliminium ions A and B, which upon reduction
with NaBH4/MeOH, produced the trans-isomers a and b
through diastereoselective anti-addition (with respect to
C1 or C2 substituents) of hydride source.
For the preparation of starting unsymmetrical phenethylsuccinimides
1 and 3, see the Supporting Information.
TfOH-Mediated Cyclization Followed by NaBH4/MeOH Reduction
of the Imides 1a–h; General Procedure
In conclusion, we have disclosed the regioselective cy-
clization of unsymmetrically substituted N-phenethyl- and
N-(3-indolylethyl)succinimides by TfOH followed by diaste-
reoselective reduction (using NaBH4) to generate pharma-
cologically valuable pyrroloisoquinolinones and indolizino-
indolones. The regio- and diastereoselectivity of the reac-
An oven-dried two-neck round-bottom flask bearing a septum in the
side arm was cooled to r.t. under a steady stream of N2 gas flow. The
flask was charged with a stirring bar, imide 1 (0.5 mmol), and anhyd
CH2Cl2 (15 mL), and cooled down to 0 °C (using ice). To this solution
was added TfOH (0.2 mL, 2 mmol) with stirring. After 30 min, the re-
action mixture was quenched with H2O (10 mL) followed by solid
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G
J. Selvakumar et al.
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Synthesis
NaHCO3 (1 g). The organic layer was separated and the aqueous layer
was extracted with CH2Cl2 (2 × 15 mL). The combined organic extracts
were washed with brine, dried (Na2SO4), filtered, and the solvent was
removed under vacuum on a rotary evaporator to dryness. The dried
compound was purified by a short silica gel column chromatography
using EtOAc and hexane as eluent.
1-Propyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2bb)
Yield: 20 mg (14%).
IR (KBr): 2949, 2849, 1692, 1612, 1512, 1447, 1362 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.62 (s, 1 H), 6.51 (s, 1 H), 4.87 (d, J =
5.6 Hz, 1 H), 4.35 (ddd, J = 12.8, 5.6, 2.0 Hz, 1 H), 3.88 (s, 3 H), 3.87 (s,
3 H), 2.91–2.83 (m, 1 H), 2.77 (td, J = 15.1, 5.0 Hz, 1 H), 2.68–2.53 (m, 3
H), 2.34 (d, J = 16.0 Hz, 1 H), 1.30–1.25 (m, 1 H), 1.16–1.07 (m, 1 H),
1.0–0.9 (m, 1 H), 0.85–0.81 (m, 1 H), 0.76 (t, J = 7.2 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 173.1, 148.1, 147.8, 127.1, 125.4,
111.8, 108.8, 60.6, 56.1, 55.9, 37.9, 37.5, 36.8, 29.8, 28.7, 19.7, 14.0.
2-Methyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2aa)
Following the general procedure, the imide 1a (138 mg, 0.5 mmol)
furnished the compounds 2aa and 2ab as colorless semisolids after
purification of the crude product mixture by silica gel column chro-
matography using EtOAc and hexane (30:70) as eluent.
8,9-Dimethoxy-2-(3,5-dimethoxybenzyl)-1,5,6,10b-tetrahydro-
2H-pyrrolo[2,1-a]isoquinolin-3(2H)-one (2ca)
Yield: 76 mg (58%).
IR (KBr): 2933, 2837, 1685, 1609, 1514, 1457, 1271, 1227, 1121, 1008,
Following the general procedure, the imide 1c (207 mg, 0.5 mmol)
furnished the compound 2ca as a colorless semisolid after purifica-
tion of the crude product mixture by silica gel column chromatogra-
phy using EtOAc and hexane (50:50) as eluent; yield: 330 mg (83%).
858 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.61 (s, 1 H), 5.56 (s, 1 H), 4.61 (dd, J =
9.3, 6.6 Hz, 1 H), 4.29 (ddd, J = 12.7, 6.0, 2.2 Hz, 1 H), 3.86 (s, 3 H), 3.86
(s, 3 H), 3.06–2.98 (m, 1 H), 2.91–2.79 (m, 2 H), 2.70–2.60 (m, 2 H),
1.44 (td, J = 11.6, 9.7 Hz, 1 H), 1.22 (d, J = 7.04 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.44, 148.2, 148.0, 129.4, 125.6,
111.8, 107.8, 56.2, 56.0, 54.6, 37.8, 37.4, 37.2, 28.3, 15.8.
IR (KBr): 1997, 2934, 2836, 1690, 1594, 1514, 1430, 1362, 1256, 1116,
956 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.60 (s, 1 H), 6.49 (s, 1 H), 6.35 (d, J =
2.2 Hz, 1 H), 6.31 (t, J = 2.2 Hz, 1 H), 4.57 (dd, J = 8.9, 6.9 Hz, 1 H), 4.32
(ddd, J = 12.7, 6.0, 2.0 Hz, 1 H), 3.85 (s, 1 H), 3.83 (s, 3 H), 3.76 (s, 6 H),
3.6 (dd, J = 13.9, 3.7 Hz, 1 H), 3.06–2.99 (m, 1 H), 2.91–2.82 (m, 2 H),
2.70–2.60 (m, 2 H), 2.41 (dd, J = 13.9, 10.7 Hz, 1 H), 1.53–1.45 (m, 1 H).
HRMS-ESI: m/z [M + Na] calcd for C15H19NO3Na+: 284.1263; found:
284.1261.
1-Methyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2ab)
13C NMR (100 MHz, CDCl3): δ = 173.9, 160.9, 148.2, 148.0, 142.3,
129.1, 125.4, 111.8, 107.8, 107.3, 106.9, 98.1, 56.1, 56.0, 55.4, 54.8,
44.9, 37.4, 37.2, 35.2, 28.3.
Yield: 40 mg (31%).
IR (KBr): 2963, 2934, 2836, 1686, 1604, 1515, 1456, 1255, 1121, 1022,
854, 796 cm–1
.
2-Methyl-8,10-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2da)
1H NMR (400 MHz, CDCl3): δ = 6.61 (s, 1 H), 6.51 (s, 1 H), 4.84 (d, J =
4.8 Hz, 1 H), 4.38–4.33 (m, 1 H), 3.84 (s, 6 H), 2.88 (tdd, J = 12.1, 3.6,
1.0 Hz, 1 H), 2.83–2.73 (m, 3 H), 2.66–2.63 (m, 1 H), 2.18–2.12 (m, 1
H), 0.61 (d, J = 7.2 Hz, 1 H).
Following the general procedure, the imide 1d (138 mg, 0.5 mmol)
furnished the compounds 2da and 2db as colorless semisolids after
purification of the crude product mixture by silica gel column chro-
matography using EtOAc and hexane (30:70) as eluent.
13C NMR (100 MHz, CDCl3): δ = 173.1, 148.3, 147.9, 127.2, 125.5,
Yield: 93 mg (71%); mp 116–118 °C.
111.9, 108.8, 60.4, 56.2, 56.0, 40.8, 36.9, 32.8, 28.7, 15.4.
HRMS-ESI: m/z [M + Na] calcd for C15H19NO3Na+: 284.1263; found:
284.1268.
IR (KBr): 2960, 2926, 2855, 1694, 1604, 1515, 1456, 1361, 1255, 1227,
1121, 1022, 854 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.34 (d, J = 2.3 Hz, 1 H), 6.25 (d, J = 2.3
Hz, 1 H), 4.63 (dd, J = 9.7, 6.1 Hz, 1 H), 4.41–4.32 (m, 1 H), 3.80 (s, 3 H),
3.78 (s, 3 H), 3.05 (ddd, J = 12.7, 7.8, 6.1 Hz, 1 H), 2.90–2.82 (m, 2 H),
2.69–2.56 (m, 2 H), 1.29–1.21 (m, 1 H), 1.18 (d, J = 7.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 175.6, 159.2, 157.7, 135.8, 118.5,
104.6, 96.9, 55.3, 55.2, 52.8, 37.6, 37.2, 36.7, 29.8, 15.6.
2-Propyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2ba)
Following the general procedure, the imide 1b (153 mg, 0.5 mmol)
furnished the compounds 2ba and 2bb as colorless semisolids after
purification of the crude product mixture by silica gel column chro-
matography using EtOAc and hexane (30:70) as eluent.
HRMS-ESI: m/z [M + Na] calcd for C15H19NO3Na+: 284.1263; found:
Yield: 105 mg (73%).
284.1267.
IR (KBr): 2958, 2932, 2870, 1686, 1610, 1514, 1456, 1362, 1255, 1114,
1012, 855, 774 cm–1
.
1-Methyl-8,10-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2db)
1H NMR (400 MHz, CDCl3): δ = 6.60 (s, 1 H), 6.56 (s, 1 H), 4.61–4.57
(m, 1 H ), 4.28 (ddd, J = 12.8, 6.0, 2.0 Hz, 1 H), 3.85 (s, 3 H), 3.84 (s, 3
H), 3.03–2.96 (m, 1 H), 2.88–2.74 (m, 2 H), 2.68–2.54 (m, 2 H), 1.95–
1.89 (m, 1 H), 1.51–1.35 (m, 2 H), 1.33–1.23 (m, 2 H), 0.91 (t, J = 7.1
Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 174.8, 148.0, 147.8, 129.3, 125.4,
111.6, 107.6, 56.0, 55.8, 54.6, 42.6, 36.9, 35.1, 32.8, 28.1, 20.3, 13.9.
Yield: 21 mg (16%).
IR (KBr): 2960, 2925, 2848, 1689, 1607, 1457, 1436, 1211, 1149, 1104,
1054, 538 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.34 (d, J = 2.3 Hz, 1 H), 6.26 (d, J = 2.3
Hz, 1 H), 4.84 (d, J = 5.5 Hz, 1 H), 4.39–4.32 (m, 1 H), 3.81 (s, 3 H), 3.79
(s, 3 H), 3.02–2.94 (m, 1 H), 2.86–2.70 (m, 3 H), 2.67–2.62 (m, 1 H),
2.06 (d, J = 16.2 Hz, 1 H), 0.54 (d, J = 7.0 Hz, 3 H).
HRMS-ESI: m/z [M + H] calcd for C17H24NO3+: 290.1756; found:
290.1756.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

H
J. Selvakumar et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 173.0, 159.3, 157.6, 137.0, 115.0,
HRMS-ESI: m/z [M + Na] calcd for C21H23NO3Na+: 360.1576; found:
104.6, 96.5, 58.43, 55.30, 55.26, 40.1, 36.4, 31.6, 29.9, 29.6, 15.4.
360.1577.
HRMS-ESI: m/z [M + Na] calcd for C15H19NO3Na+: 284.1263; found:
284.1260.
8-Methoxy-2-(3,5-dimethoxybenzyl)-1,5,6,10b-tetrahydro-2H-
pyrrolo[2,1-a]isoquinolin-3(2H)-one (2ga)
Following the general procedure, the imide 1g (192 mg, 0.5 mmol)
furnished the compound 2ga as a colorless semisolid after purifica-
tion of the crude product mixture by silica gel column chromatogra-
phy using EtOAc and hexane (50:50) as eluent.
2-Methyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]iso-
quinolin-3(2H)-one (2ea)
Following the general procedure, the imide 1e (124 mg, 0.5 mmol)
furnished the compounds 2ea and 2eb as colorless semisolids after
purification of the crude product mixture by silica gel column chro-
matography using EtOAc and hexane (30:70) as eluent.
Yield: 143 mg (78%).
IR (KBr): 2934, 2837, 1686, 1595, 1505, 1457, 1431, 1205, 1151, 1071,
Yield: 73 mg (63%).
825 cm–1
.
IR (KBr): 2963, 2928, 2869, 2831, 1694, 1611, 1505, 1456, 1432, 1362,
1H NMR (400 MHz, CDCl3): δ = 6.95 (d, J = 8.4 Hz, 1 H), 6.77 (dd, J = 8.4,
2.6 Hz, 1 H), 6.66 (d, J = 2.6 Hz, 1 H), 6.34 (d, J = 2.2 Hz, 2 H), 6.31 (t, J =
2.2 Hz, 1 H), 4.58 (dd, J = 9.2, 6.6 Hz, 1 H), 4.27 (ddd, J = 12.8, 6.0, 2.6
Hz, 1 H), 3.78 (s, 3 H), 3.76 (s, 6 H), 3.36 (dd, J = 13.8, 3.7 Hz, 1 H),
3.12–3.04 (m, 1 H), 2.95–2.83 (m, 2 H), 2.78–2.72 (m, 1 H), 2.67–2.61
(m, 1 H), 2.41 (dd, J = 13.8, 10.5 Hz, 1 H), 1.50 (td, J = 11.4, 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 160.9, 158.4, 142.4, 134.9,
129.7, 126.1, 113.8, 113.2, 106.9, 98.2, 55.45, 55.42, 54.6, 44.9, 37.5,
37.2, 35.2, 29.0.
1309, 1270, 1239, 1156, 1037, 889, 806, 728, 582 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.02 (d, J = 8.5 Hz, 1 H), 6.80 (dd, J = 8.5,
2.4 Hz, 1 H), 6.67 (d, J = 2.4 Hz, 1 H), 4.61 (dd, J = 9.3, 6.7 Hz, 1 H), 4.23
(ddd, J = 12.8, 6.0, 2.8 Hz, 1 H), 3.78 (s, 3 H), 3.10–3.03 (m, 1 H), 2.95–
2.85 (m, 1 H), 2.83–2.71 (m, 2 H), 2.68–2.61 (m, 1 H), 1.47–1.39 (m, 1
H), 1.21 (d, J = 8.7 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.4, 158.2, 134.9, 129.8, 125.9,
113.6, 113.1, 55.3, 54.3, 37.6, 37.3, 37.0, 28.9, 15.6.
HRMS-ESI: m/z [M + Na] calcd for C22H25NO4Na+: 390.1681; found:
390.1684.
HRMS-ESI: m/z [M + Na] calcd for C14H17NO2Na+: 254.1157; found:
254.1155.
8-Methoxy-2-(3-methoxybenzylidene)-1,5,6,10b-tetrahydro-2H-
pyrrolo[2,1-a]isoquinolin-3(2H)-one (2ha)
1-Methyl-8-methoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-a]iso-
quinolin-3(2H)-one (2eb)
Following the general procedure, the imide 1h (176 mg, 0.5 mmol)
furnished the compound 2ha as a colorless semisolid after purifica-
tion of the crude product mixture by silica gel column chromatogra-
phy using EtOAc and hexane (40:60) as eluent.
Yield: 16 mg (14%).
IR (KBr): 2963, 2928, 2866, 2834, 1697, 1612, 1434, 1362, 1243, 1311,
1243, 1034, 918, 813, 770, 586 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.97 (d, J = 8.5 Hz, 1 H), 6.81 (dd, J = 8.5,
2.4 Hz, 1 H), 6.66 (d, J = 2.1 Hz, 1 H), 4.86 (d, J = 4.9 Hz, 1 H), 4.38–4.33
(m, 1 H), 3.79 (s, 3 H), 2.92–2.86 (m, 1 H), 2.82–2.68 (m, 4 H), 2.14 (d,
J = 15.4 Hz, 1 H), 0.59 (d, J = 6.9 Hz, 3 H).
Yield: 100 mg (60%).
IR (KBr): 2998, 2963, 2849, 1686, 1649, 1589, 1505, 1455, 1427, 1264,
1064, 801, 681 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.30 (t, J = 2.7 Hz, 1 H), 7.12 (d, J = 8.5
Hz, 1 H), 6.83 (dd, J = 8.5, 2.7 Hz, 1 H), 6.67 (d, J = 2.6 Hz, 1 H), 6.63 (d,
J = 2.2 Hz, 1 H), 6.45 (t, J = 2.2 Hz, 1 H), 4.85–4.81 (m, 1 H), 4.46 (ddd,
J = 12.9, 6.2, 2.2 Hz, 1 H), 3.82 (s, 6 H), 3.78 (s, 3 H), 3.76–3.74 (m, 1 H),
3.68 (ddd, J = 17.0, 7.9, 2.3 Hz, 1 H), 3.21 (ddd, J = 12.9, 11.4, 4.6 Hz, 1
H), 3.07–2.98 (m, 1 H), 2.94 (ddd, J = 17.0, 5.3, 3.2 Hz, 1 H), 2.80–2.76
(m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 167.6, 160.8, 158.5, 137.6, 135.2,
131.7, 130.0, 129.7, 126.3, 113.7, 113.2, 107.8, 100.4, 55.4, 53.3, 54.3,
37.7, 33.7, 29.7, 28.7.
13C NMR (100 MHz, CDCl3): δ = 172.9, 158.0, 136.0, 127.2, 125.8,
113.6, 113.2, 60.1, 55.2, 40.6, 36.5, 32.6, 29.3, 15.3.
HRMS-ESI: m/z [M + Na] calcd for C14H17NO2Na+: 254.1157; found:
254.1160.
8-Methoxy-2-(3-methoxybenzyl)-1,5,6,10b-tetrahydro-2H-pyrro-
lo[2,1-a]isoquinolin-3(2H)-one (2fa)
Following the general procedure, the imide 1f (177 mg, 0.5 mmol)
furnished the compound 2fa as a colorless semisolid after purifica-
tion of the crude product mixture by silica gel column chromatogra-
phy using EtOAc and hexane (50:50) as eluent.
HRMS-ESI: m/z [M + Na] calcd for C22H23NO4Na+: 388.1525; found:
388.1594.
Yield: 99 mg (56%).
IR (KBr): 1997, 2934, 2836, 1690, 1594, 1514, 1430, 1362, 1256, 1116,
TfOH-Mediated Cyclization Followed by NaBH4/MeOH Reduction
of the Imides 3a–g; General Procedure
1956, 829 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.21–7.17 (m, 1 H), 6.96 (d, J = 10.5 Hz,
1 H), 6.78–6.74 (m, 4 H), 6.66 (d, J = 2.3 Hz, 1 H), 4.58 (dd, J = 9.2, 6.8
Hz, 1 H), 4.28 (ddd, J = 12.8, 6.0, 2.6 Hz, 1 H), 3.78 (s, 6 H), 3.39 (dd, J =
13.8, 3.7 Hz, 1 H), 3.11–3.04 (m, 1 H), 2.95–2.85 (m, 2 H), 2.78–2.73
(m, 1 H), 2.65–2.59 (m, 1 H), 2.45 (dd, J = 13.8, 10.7 Hz, 1 H), 1.50 (td,
J = 11.6, 9.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 174.0, 159.7, 158.3, 141.4, 134.8,
129.5, 129.4, 125.9, 121.2, 114.5, 113.6, 113.1, 111.5, 55.3, 55.1, 54.5,
44.9, 37.1, 37.0, 35.0, 28.9.
A 50 mL two-neck round-bottom flask was charged with imide 3 (0.7
mmol), 4Å molecular sieves (50 mg), anhyd CH2Cl2 (20 mL), and a stir
bar. The flask was capped with a rubber septum and maintained un-
der N2 atmosphere. TfOH (7.6 mmol) was added and the mixture
stirred at r.t. for 12 h. To this mixture were added NaBH4 (3.8 mmol)
and MeOH (5 mL) and stirred for 0.5 h under N2 atmosphere. Then the
mixture was quenched with aq NaHCO3. The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (3 × 50 mL).
The combined organic layers were washed with aq NaHCO3, dried
(Na2SO4), and filtered. The solvent was removed under reduced pres-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

I
J. Selvakumar et al.
Paper
Synthesis
sure. The crude mixture was purified by column chromatography on
neutral alumina using EtOAc/hexane (25:75) mixture as eluent to give
4aa–ga and using EtOAc/hexane (30:70) mixture as eluent to give
4ab–gb in pure form.
HRMS-ESI: m/z [M + H]+ calcd for C21H19FN2O: 335.1554; found:
335.1550.
1-Benzyl-8-fluoro-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4bb)
2-Benzyl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]indol-3-
one (4aa)
Yield: 119 mg (54%); mp 273–274 °C.
IR (KBr): 3487, 2974, 2893, 1671, 1427, 1312, 1182, 960 cm–1
.
Following the general procedure, the imide 3a (253 mg, 0.7 mmol)
furnished the compounds 4aa and 4ab as off-white solids.
1H NMR (400 MHz, CDCl3): δ = 7.76 (br s, 1 H), 7.21–7.13 (m, 5 H),
6.99 (d, J = 1.6 Hz, 1 H), 6.97 (d, J = 1.2 Hz, 1 H), 6.92 (td, J = 8.8, 2.4 Hz,
1 H), 5.08 (d, J = 6.0 Hz, 1 H), 4.58–4.54 (m, 1 H), 3.05-2.93 (m, 2 H),
2.86–2.84 (m, 2 H), 2.63 (dd, J = 16.4, 6.8 Hz, 1 H), 2.56 (dd, J = 14.4,
5.2 Hz, 1 H), 2.30 (d, J = 16.4 Hz, 1 H), 2.19 (dd, J = 14.0, 10.4 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.79, 158.12 (d, J = 234.0 Hz, 1 C),
138.99, 133.14, 131.79, 128.99, 128.70, 127.33 (d, J = 10.0 Hz, 1 C),
126.50, 111.81 (d, J = 10.0 Hz, 1 C), 111.24 (d, J = 4.0 Hz, 1 C), 110.68
(d, J = 26.0 Hz, 1 C), 103.72 (d, J = 23.0 Hz, 1 C), 57.96, 38.49, 37.65,
37.59, 35.34, 21.32.
Yield: 63 mg (26%); mp 217–218 °C.
IR (KBr): 3276, 2924, 2851, 1700, 1496, 1434, 1304, 1176 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.98 (br s, 1 H), 7.49 (d, J = 7.6 Hz, 1 H),
7.32–7.26 (m, 2 H), 7.23–7.22 (m, 1 H), 7.20–7.18 (m, 1 H), 7.17–7.14
(m, 2 H), 7.12–7.10 (m, 2 H), 4.76 (dd, J = 9.2, 6.8 Hz, 1 H), 4.58–4.53
(m, 1 H), 3.41 (dd, J = 14.0, 4.0 Hz, 1 H), 3.08–3.00 (m, 1 H), 2.97–2.89
(m, 1 H), 2.83 (ddd, J = 9.2, 4.4, 2.0 Hz, 2 H), 2.50 (dd, J = 14.4, 12.0 Hz,
1 H), 2.49 (dd, J = 14.0, 10.8 Hz, 1 H), 1.60 (td, J = 11.6, 9.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.88, 139.65, 136.37, 133.14,
128.90, 128.66, 126.95, 126.47, 122.41, 120.05, 118.59, 111.10,
108.24, 52.36, 44.95, 37.71, 37.13, 33.14, 21.24.
HRMS-ESI: m/z [M + H]+ calcd for C21H19FN2O: 335.1554; found:
335.1554.
HRMS-ESI: m/z [M + H]+ calcd for C21H20N2O: 317.1648; found:
317.1649.
2-Benzyl-8-bromo-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4ca)
Following the general procedure, the imide 3c (230 mg, 0.6 mmol)
furnished the compounds 4ca and 4cb as pale yellow solids.
1-Benzyl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]indol-3-
one (4ab)
Yield: 46 mg (21%); mp 212–213 °C.
Yield: 132 mg (55%); mp 253–254 °C.
IR (KBr): 3266, 2924, 2853, 1668, 1492, 1437, 1311 cm–1
IR (KBr): 3243, 2923, 2852, 1669, 1432, 1304, 1050, 699 cm–1
.
.
1H NMR (400 MHz, CDCl3): δ = 7.89 (br s, 1 H), 7.61 (d, J = 2.0 Hz, 1 H),
7.27 (d, J = 1.6 Hz, 1 H), 7.25–7.23 (m, 3 H), 7.19–7.15 (m, 4 H), 4.75
(dd, J = 9.2, 6.8 Hz, 1 H), 4.58–4.53 (m, 1 H), 3.41 (dd, J = 14.0, 4.0 Hz, 1
H), 3.07–2.90 (m, 2 H), 2.79 (ddd, J = 9.2, 5.2, 2.0 Hz, 1 H), 2.55–2.48
(m, 2 H), 1.65–1.57 (m, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.81, 139.54, 134.98, 134.46,
128.91, 128.78, 128.67, 126.52, 125.22, 121.34, 113.28, 112.48,
108.11, 52.18, 44.86, 37.56, 37.07, 32.91, 21.10.
1H NMR (400 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.53 (d, J = 7.6 Hz, 1 H),
7.30 (d, J = 7.6 Hz, 1 H), 7.22–7.13 (m, 5 H), 7.02–7.00 (m, 2 H), 5.11
(d, J = 5.6 Hz, 1 H), 4.58 (ddd, J = 12.4, 4.8, 1.2 Hz, 1 H), 3.08–2.95 (m, 2
H), 2.92–2.83 (m, 2 H), 2.65–2.57 (m, 2 H), 2.30 (d, J = 16.4 Hz, 1 H),
2.17 (dd, J = 14.4, 10.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.89, 139.13, 136.78, 129.91,
129.04, 128.65, 126.93, 126.45, 122.47, 119.99, 118.51, 111.25,
110.90, 58.13, 38.44, 37.79, 37.48, 35.23, 21.37.
HRMS-ESI: m/z [M + H]+ calcd for C21H19BrN2O: 395.0753; found:
395.0755.
HRMS-ESI: m/z [M + H]+ calcd for C21H20N2O: 317.1648; found:
317.1649.
1-Benzyl-8-bromo-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4cb)
2-Benzyl-8-fluoro-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4ba)
Yield: 111 mg (50%); mp 257–258 °C.
Following the general procedure, the imide 3b (230 mg, 0.7 mmol)
furnished the compounds 4ba as a viscous liquid and 4bb as a color-
less solid.
IR (KBr): 3167, 2901, 1673, 1423, 1307, 1188, 791 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.94 (br s, 1 H), 7.64 (s, 1 H), 7.25 (d, J =
5.2 Hz, 1 H), 7.20–7.15 (m, 3 H), 7.12 (d, J = 8.4 Hz, 1 H), 6.97 ( d, J = 7.2
Hz, 2 H), 5.08 (d, J = 5.6 Hz, 1 H), 4.58–4.54 (m, 1 H), 3.06–2.90 (m, 2
H), 2.88–2.78 (m, 2 H), 2.64 (dd, J = 16.8, 6.8 Hz, 1 H), 2.54 (dd, J =
14.0, 5.6 Hz, 1 H), 2.30 (d, J = 16.8 Hz, 1 H), 2.20 (dd, J = 14.0, 10.0 Hz,
1 H).
13C NMR (100 MHz, CDCl3): δ = 173.83, 139.55, 135.03, 134.50,
128.93, 128.83, 128.68, 126.53, 125.23, 121.35, 113.30, 112.49,
108.14, 52.22, 44.86, 37.58, 37.09, 32.91, 21.11.
Yield: 50 mg (23%).
IR (KBr): 3171, 2976, 2896, 1670, 1427, 1309, 1183, 958 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.82 (br s, 1 H), 7.28–7.27 (m, 1 H),
7.25–7.15 (m, 4 H), 7.12 (dd, J = 9.6, 2.4 Hz, 2 H), 6.92 (td, J = 8.8, 2.4
Hz, 1 H), 4.76 (dd, J = 9.2, 6.8 Hz, 1 H), 4.55 (ddd, J = 13.2, 5.2, 2.4 Hz, 1
H), 3.42 (dd, J = 13.6, 4.0 Hz, 1 H), 3.08–3.01 (m, 1 H), 2.98–2.90 (m, 1
H), 2.82–2.78 (m, 2 H), 2.52 (dd, J = 12.0, 1.2 Hz, 1 H), 2.51 (dd, J =
14.0, 11.2 Hz, 1 H), 1.61 (td, J = 11.6, 9.2 Hz, 1 H).
HRMS-ESI: m/z [M + H]+ calcd for C21H19BrN2O: 395.0753; found:
13C NMR (100 MHz, CDCl3): δ = 173.83, 158.04 (d, J = 234.0 Hz, 1 C),
139.59, 135.07, 132.84, 128.92, 128.67, 127.50 (d, J = 10.0 Hz, 1 C),
126.51, 111.65 (d, J = 10.0 Hz, 1 C), 110.58 (d, J = 26.0 Hz, 1 C), 108.61
(d, J = 5.0 Hz, 1 C), 103.81 (d, J = 23.0 Hz, 1 C), 52.32, 44.68, 37.63,
37.12, 32.97, 21.20.
395.0749.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

J
J. Selvakumar et al.
Paper
Synthesis
2-Benzyl-10-methyl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4da)
IR (KBr): 3293, 2925, 2858, 1674, 1446, 1314, 1084 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.61 (br s, 1 H), 7.19–7.15 (m, 4 H),
6.98–6.96 (m, 2 H), 6.83 (s, 1 H), 5.10 (d, J = 5.6 Hz, 1 H), 4.57–4.52 (m,
1 H), 3.08–3.02 (m, 1 H), 2.98–2.92 (m, 1 H), 2.89–2.83 (m, 2 H), 2.66
(dd, J = 16.4, 7.6 Hz, 1 H), 2.60 (dd, J = 14.4, 6.0 Hz, 1 H), 2.43 (s, 3 H),
2.35 (s, 3 H), 2.31 (d, J = 16.4 Hz, 1 H), 2.24 (dd, J = 14.4, 10.0 Hz, 1 H).
Following the general procedure, the imide 3d (205 mg, 0.6 mmol)
furnished the compounds 4da as a viscous liquid and 4db as a color-
less solid.
Yield: 72 mg (37%).
13C NMR (100 MHz, CDCl3): δ = 172.90, 139.28, 134.57, 129.70,
129.58, 128.92, 128.61, 126.68, 126.34, 124.82, 120.00, 115.83,
111.11, 58.19, 38.52, 37.92, 37.85, 35.44, 21.51, 21.47, 16.75.
HRMS-ESI: m/z [M + H]+ calcd for C23H24N2O: 345.1961; found:
345.1961.
IR (KBr): 3284, 2923, 2855, 1347, 1670, 1454, 1435 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.25 (d, J = 8.0 Hz, 1 H),
7.16–7.04 (m, 5 H), 6.97 (t, J = 7.6 Hz, 1 H), 6.90 (d, J = 7.2 Hz, 1 H),
4.68 (dd, J = 8.8, 6.8 Hz, 1 H), 4.67–4.42 (m, 1 H), 3.31 (dd, J = 14.0, 4.0
Hz, 1 H), 2.96–2.89 (m, 1 H), 2.87–2.78 (m, 1 H), 2.74–2.72 (m, 2 H),
2.49–2.43 (m, 1 H), 2.39 (s, 3 H), 2.37 (dd, J = 13.6, 10.8 Hz, 1 H), 1.52
(td, J = 11.6, 9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.95, 139.59, 135.91, 132.90,
128.83, 128.60, 126.44, 126.41, 122.95, 120.33, 120.14, 116.17,
108.45, 52.51, 44.91, 37.75, 37.11, 33.29, 21.33, 16.81.
2-Benzyl-8-methoxy-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4fa)
Following the general procedure, the imide 3f (220 mg, 0.6 mmol)
furnished the compounds 4fa and 4fb as viscous liquids.
HRMS-ESI: m/z [M + H]+ calcd for C22H22N2O: 331.1804; found:
Yield: 78 mg (37%).
IR (KBr,): 3352, 2925, 1672, 1596, 1490, 1432, 1215, 1031 cm–1
.
331.1804.
1H NMR (400 MHz, CDCl3): δ = 7.75 (br s, 1 H), 7.28–7.27 (m, 1 H),
7.24–7.15 (m, 5 H), 6.93 (d, J = 2.0 Hz, 1 H), 6.83 (dd, J = 8.8, 2.4 Hz, 1
H), 4.74 (dd, J = 8.8, 6.8 Hz, 1 H), 4.56 (ddd, J = 2.4, 4.4, 13.2 Hz, 1 H),
3.86 (s, 3 H), 3.41 (dd, J = 13.6, 4.0 Hz, 1 H), 3.08–3.01 (m, 1 H), 2.97–
2.85 (m, 1 H), 2.83–2.77 (m, 2 H), 2.53–2.46 (m, 2 H), 1.60 (td, J = 11.6,
9.6 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 173.92, 154.48, 139.65, 134.01,
131.40, 128.90, 128.65, 127.40, 126.46, 112.27, 111.80, 108.07,
100.73, 56.07, 52.43, 44.92, 37.72, 37.12, 33.11, 21.29.
1-Benzyl-10-methyl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4db)
Yield: 66 mg (34%); mp 252–253 °C.
IR (KBr): 3430, 2918, 2854, 1669, 1439, 1344, 741 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 7.48 (br s, 1 H), 7.37 (d, J = 8.0 Hz, 1 H),
7.17–7.15 (m, 3 H), 7.06 (t, J = 7.6 Hz, 1 H), 7.00–6.95 (m, 3 H), 5.11 (d,
J = 5.6 Hz, 1 H), 4.56 (ddd, J = 12.0, 3.6, 2.4 Hz, 1 H), 3.11–3.04 (m, 1 H),
3.00–2.87 (m, 3 H), 2.68 (dd, J = 16.8, 6.8 Hz, 1 H), 2.60 (dd, J = 14.4,
10.4 Hz, 1 H), 2.37 (s, 3 H), 2.32 (d, J = 16.8 Hz, 1 H), 2.28 (dd, J = 14.4,
9.6 Hz, 1 H).
HRMS-ESI: m/z [M + H]+ calcd for C22H22N2O2: 347.1754; found:
347.1754.
13C NMR (100 MHz, CDCl3): δ = 172.92, 139.23, 136.25, 129.57,
128.91, 128.62, 126.42, 126.37, 123.17, 120.33, 120.25, 116.19,
111.66, 58.12, 38.56, 38.01, 37.84, 35.56, 21.47, 16.80.
1-Benzyl-8-methoxy-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-
b]indol-3-one (4fb)
HRMS-ESI: m/z [M + H]+ calcd for C22H22N2O: 331.1805; found:
Yield: 74 mg (35%).
IR (KBr): 3318, 2921, 1670, 1632, 1432, 1216, 1032 cm–1
.
331.1805.
1H NMR (400 MHz, CDCl3): δ = 8.19 (br s, 1 H), 7.22–7.13 (m, 4 H),
7.01–6.99 (m, 2 H), 6.98 (d, J = 2.4 Hz, 1 H), 6.84 (dd, J = 8.8, 2.4 Hz, 1
H), 5.08 (d, J = 6.0 Hz, 1 H), 4.59–4.54 (m, 1 H), 3.87 (s, 3 H), 3.03–2.95
(m, 2 H), 2.88–2.84 (m, 2 H), 2.63–2.57 (m, 2 H), 2.30 (d, J = 16.4 Hz, 1
H), 2.16 (dd, J = 11.2, 2.8 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.92, 154.41, 139.14, 131.81,
130.77, 129.04, 128.63, 127.31, 126.41, 112.35, 111.97, 110.59,
100.59, 58.17, 56.07, 38.45, 37.78, 37.43, 35.17, 21.43.
2-Benzyl-8,10-dimethyl-1,2,5,6,11,11b-hexahydro-3H-indoliz-
ino[8,7-b]indol-3-one (4ea)
Following the general procedure, the imide 3e (220 mg, 0.6 mmol)
furnished the compounds 4ea as a viscous liquid and 4eb as a color-
less solid.
Yield: 74 mg (37%).
IR (KBr): 3249, 2916, 2852, 1671, 1437, 1310, 1186 cm–1
.
HRMS-ESI: m/z [M + H]+ calcd for C22H22N2O2: 347.1755, found:
347.1755.
1H NMR (400 MHz, CDCl3): δ = 7.60 (br s, 1 H), 7.29–7.27 (m, 1 H),
7.25–7.24 (m, 1 H), 7.18 (td, J = 6.8, 1.6 Hz, 3 H), 7.13 (s, 1 H), 6.83 (s, 1
H), 4.77 (dd, J = 9.2, 6.8 Hz, 1 H), 4.58–4.53 (m, 1 H), 3.43 (dd, J = 14.0,
4.0 Hz, 1 H), 3.07–3.01 (m, 1 H), 3.00–2.90 (m, 1 H), 2.83–2.79 (m, 2
H), 2.56–2.52 (m, 1 H), 2.51–2.49 (m, 1 H), 2.42 (s, 6 H), 1.62–1.56 (m,
1 H).
13C NMR (100 MHz, CDCl3): δ = 173.89, 139.76, 134.18, 132.98,
129.68, 128.93, 128.67, 126.80, 126.47, 124.78, 119.90, 115.99,
108.43, 52.46, 44.93, 37.76, 37.15, 33.26, 21.50, 21.35, 16.72.
2-Benzhydryl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]in-
dol-3-one (4ga)
Following the general procedure, the imide 3g (250 mg, 0.6 mmol)
furnished the compounds 4ga and 4gb as pale brown solids.
Yield: 55 mg (23%); mp 254–255 °C.
IR (KBr): 3425, 2925, 2830, 1629, 1355 cm–1
.
HRMS-ESI: m/z [M + H]+ calcd for C23H24N2O: 345.1961; found:
345.1961.
1H NMR (400 MHz, CDCl3): δ = 7.72 (br s, 1 H), 7.44 (d, J = 7.6 Hz, 1 H),
7.31 (d, J = 4.0 Hz, 4 H), 7.25–7.10 (m, 4 H), 7.07–7.04 (m, 4 H), 6.95–
6.94 (m, 1 H), 4.83–4.79 (m, 1 H), 4.59 (d, J = 6.0 Hz, 1 H), 4.50 (dd, J =
13.2, 4.8 Hz, 1 H), 3.60–3.53 (m, 1 H), 3.00 (td, J = 11.2, 4.8 Hz, 1 H),
2.77–2.68 (m, 2 H), 2.65–2.59 (m, 1 H), 1.78–1.70 (m, 1 H).
1-Benzyl-8,10-dimethyl-1,2,5,6,11,11b-hexahydro-3H-indoliz-
ino[8,7-b]indol-3-one (4eb)
Yield: 82 mg (39%); mp 236–237 °C.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

K
J. Selvakumar et al.
Paper
Synthesis
13C NMR (100 MHz, CDCl3): δ = 173.24, 143.46, 142.02, 136.29,
132.90, 128.88, 128.54, 128.35 (2 C merging), 127.03, 126.61, 126.49,
122.31, 119.97, 118.51, 111.01, 108.47, 52.18, 51.16, 46.83, 37.78,
30.92, 21.13.
HRMS-ESI: m/z [M + H]+ calcd for C27H24N2O: 393.1961; found:
393.1962.
Acknowledgment
We thank CSIR and DST for financial support. J. S. thanks CSIR (New
Delhi) and S. M. R thanks UGC (New Delhi) for a Senior Research Fel-
lowhip. The authors gratefully acknowledge Prof. K. R. Prasad, I.I.Sc.,
Bengaluru and Prof. D. B. Ramachary, University of Hyderabad for
HRMS analysis. We gratefully acknowledge DST-FIST sponsored single
crystal XRD and HRMS facilities, Department of Chemistry; Central
Instrumentation Faculty, Pondicherry University for NMR/IR data;
and DBT-IPLS Programme, Pondicherry University.
1-Benzhydryl-1,2,5,6,11,11b-hexahydro-3H-indolizino[8,7-b]in-
dol-3-one (4gb)
Yield: 151 mg (63%); mp 230–231 °C.
IR (KBr): 3419, 2924, 2830, 1705, 1628, 1592, 1490, 1350 cm–1
.
Supporting Information
1H NMR (400 MHz, CDCl3): δ = 7.44 (d, J = 7.6 Hz, 1 H), 7.38–7.37 (m, 2
H), 7.33 (t, J = 7.6 Hz, 2 H), 7.25–7.22 (m, 3 H), 7.17–7.12 (m, 3 H),
7.11–7.05 (m, 2 H), 6.97–6.95 (m, 2 H), 5.24 (d, J = 6.8 Hz, 1 H), 4.50–
4.45 (m, 1 H), 4.00 (d, J = 11.6 Hz, 1 H), 3.76–3.67 (m, 1 H), 3.00–2.90
(m, 2 H), 2.75–2.71 (m, 1 H), 2.32 (dd, J = 17.2, 8.0 Hz, 1 H), 2.19 (dd,
J = 17.2, 8.0 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 174.53, 143.23, 143.14, 136.39,
129.81, 129.62, 129.07, 127.80, 127.55, 127.45, 127.01, 126.54,
122.38, 119.71, 118.30, 111.99, 111.09, 58.52, 52.46, 41.00, 39.20,
37.17, 20.84.
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0036-1588639.
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References
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HRMS-ESI: m/z [M + H]+ calcd for C27H24N2O+: 393.1961; found:
393.1966.
2-Propyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2ba + 2ba′)
The partial reduction was conducted with imide 1b (153 mg, 0.5
mmol) using NaBH4/MeOH and the mixture of hydroxy lactams were
subjected to N-acyliminium ion cyclization using TFA;13 yield: 45 mg
(31%); colorless viscous liquid.
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IR (KBr): 2962, 2856, 1683, 1606, 1514, 1459, 1368 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.57–6.65 (m, 1 H), 6.54–6.53 (m, 1 H),
4.68 (t, J = 7.6 Hz, 0.65 H), 4.99–4.55 (m, 0.31 H ), 4.28–4.23 (m, 1 H),
3.82 (s, 3 H), 3.81 (s, 3 H), 3.00–2.93 (m, 1 H), 2.85–2.77 (m, 1.4 H),
2.63–2.59 (m, 1 H), 2.48–2.46 (m, 1 H), 2.23–2.31 (m, 0.66 H), 2.02–
1.97 (m, 0.36 H), 1.68–1.78 (m, 0.7 H), 1.48–1.23 (m, 3 H), 0.94–0.87
(m, 3 H).
13C NMR (100 MHz, CDCl3): δ = 175.7, 174.8, 148.10, 148.0, 147.8,
129.6, 129.3, 125.6, 125.4, 111.7, 107.7, 56.0, 55.9, 55.1, 54.6, 42.8,
42.7, 37.2, 37.0, 35.2, 33.4, 33.1, 32.9, 28.2, 28.0, 20.7, 20.4, 14.0,
13.98.
1-Propyl-8,9-dimethoxy-1,5,6,10b-tetrahydro-2H-pyrrolo[2,1-
a]isoquinolin-3(2H)-one (2bb′)
Yield: 29 mg (20%); colorless viscous liquid.
IR (KBr): 2928, 2862, 1686, 1607, 1514, 1456, 1367 cm–1
.
1H NMR (400 MHz, CDCl3): δ = 6.70 (s, 1 H), 6.60 (s, 1 H), 4.36 (d, J =
6.4 Hz, 1 H), 4.26–4.21 (m, 1 H), 3.85 (s, 3 H), 3.84 (s, 3 H), 3.00–2.97
(m, 1 H), 2.90–2.82 (m, 1 H), 2.63–2.54 (m, 2 H), 2.26–2.19 (m, 2 H),
1.98–1.91 (m, 1 H), 1.63–1.59 (m, 1 H), 1.51–1.47 (m, 1 H), 1.42–1.34
(m, 1 H), 0.98 (t, J = 7.2 Hz, 1 H).
13C NMR (100 MHz, CDCl3): δ = 172.8, 148.0, 147.9, 129.4, 126.5,
111.9, 107.9, 62.2, 56.1, 56.00, 41.0, 38.1, 37.7, 37.4, 28.4, 20.9, 14.2.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L

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J. Selvakumar et al.
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Synthesis
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© Georg Thieme Verlag Stuttgart · New York — Synthesis 2016, 48, A–L