Advancing the morita-baylis-hillman chemistry of 1-formyl-ss- carbolines for the synthesis of indolizino-indole derivatives

Article abstract of DOI:10.1002/ejoc.201000322

The chemistry of the Morita-Baylis-Hillman adducts of 1formyl-ss- carbolines has been, extended for obtaining indolizino-indole derivatives which mimic the harmicine and homofascaplysin frameworks. Adducts of N-substituted methyl 1formyl-9H-ss-carboline-3-carboxylate yield indolizino-indole derivatives upon bromination followed by aqueous workup. On the other hand, N-substituted l-formyl-9H-ss-carbolines give rise to similar products in a one-pot DABCO-promoted reaction of activated alkenes. Alternatively, the DMAP-mediated Morita-Baylis-Hillman reaction of N-substituted methyl l-formyl-9H-ss-carboline-3-carboxylate with cycloalkenories yields adducts that cyclize intramolecularly in the presence of PBr₃ to yield compounds with the homofascaplysin framework. In contrast, the DMAP-mediated reaction of N-substituted l-formyl-ss-carboline with cyclohexenone directly gives a product with similar framework in a single step.

Full text of DOI:10.1002/ejoc.201000322

FULL PAPER
DOI: 10.1002/ejoc.201000322
Advancing the Morita–Baylis–Hillman Chemistry of 1-Formyl-β-carbolines for
the Synthesis of Indolizino-indole Derivatives[‡]
Virender Singh,[a] Samiran Hutait,[a] and Sanjay Batra*[a]
Keywords: Nitrogen heterocycles / Alkaloids / Morita–Baylis–Hillman reaction / Harmicine / Homofascaplysin
The chemistry of the Morita–Baylis–Hillman adducts of 1-
formyl-β-carbolines has been extended for obtaining indoliz-
ino-indole derivatives which mimic the harmicine and homo-
fascaplysin frameworks. Adducts of N-substituted methyl 1-
formyl-9H-β-carboline-3-carboxylate yield indolizino-indole
derivatives upon bromination followed by aqueous workup.
On the other hand, N-substituted 1-formyl-9H-β-carbolines
give rise to similar products in a one-pot DABCO-promoted
reaction of activated alkenes. Alternatively, the DMAP-medi-
ated Morita–Baylis–Hillman reaction of N-substituted methyl
1-formyl-9H-β-carboline-3-carboxylate with cycloalkenones
yields adducts that cyclize intramolecularly in the presence
of PBr3 to yield compounds with the homofascaplysin frame-
work. In contrast, the DMAP-mediated reaction of N-substi-
tuted 1-formyl-β-carboline with cyclohexenone directly gives
a product with similar framework in a single step.
Indeed, the formation of indolizines from 2-pyridinecarbox-
aldehyde has been reported to take place following the lat-
ter path.[4] More importantly for our study, either pathway
would afford new annulated β-carboline system. Investiga-
ting this approach, we have discovered that the allyl bro-
mide which is generated via bromination of the MBH ad-
duct of N-substituted 1-formyl-β-carboline immediately ini-
tiates nucleophilic attack of the nitrogen of the C-ring to
furnish an indolizino-indole system which represents the
aromatized derivative of the alkaloid harmicine (Fig-
ure 2).[5] Similar reactions with cycloalkenones give prod-
Introduction
We have recently reported on the Morita–Baylis–Hillman
(MBH) reactions of 1-formyl-9H-β-carbolines with alkyl
acrylates which resulted in one-pot synthesis of unusual
canthin-6-ones.[1] Moreover, adducts derived from acryloni-
trile were readily transformed into canthine derivatives via
base-promoted intramolecular cyclization. Furthermore, in-
stalling an alkene or alkyne chain on the indole NH and
generating dipolarophile in the form of nitrile oxide, azide
or azomethine ylide from the formyl group allowed us to
construct a variety of fused β-carboline-based compounds
via cycloaddition reactions.[2] In our efforts to expand the
repertoire of fused-carbolines which could be synthesized
from substituted 1-formyl-β-carbolines, we became inter-
ested in investigating the reactivity of substrates substituted
at nitrogen by allyl and alkyne groups for 3+2 cycloaddition
reaction. In principle, the allyl bromide obtained from the
MBH reaction of such N-substituted aldehydes via bromi-
nation will lead to an allyl bromide which, under the influ-
ence of PPh3 or PBu3 may furnish a dipolarophile. This
dipolarophile can initiate an intramolecular 3+2 cycload-
dition reaction with alkene or alkyne chain on the nitrogen
leading to annulated β-carboline (path 1, Figure 1).[3] Alter-
natively, the nucleophilicity of the N atom of the C-ring of
β-carboline may initiate an intramolecular cyclization re-
sulting in an indolizino-indole system (path 2, Figure 1).
Figure 1. Retrosynthetic pathway.
[‡] CDRI Communication No. 7935.
[a] Medicinal and Process Chemistry Division, Central Drug Re-
search Institute, CSIR,
P. O. Box 173, Lucknow 226001, UP, India
Fax: +91-522-2623405
E-mail: batra-san@yahoo.co.uk, s_batra@cdri.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201000322.
Figure 2. Core structure of alkaloids harmicine and fascaplysin.
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Synthesis of Indolizino-indole Derivatives
ucts with a homofascaplysin type of ring framework.[6] We product (Figure 3). This plausible mechanism inspired us
provide an update on the results of our study in this direc- to perform a few more optimization studies. In one of the
tion.
experiments, the reaction after quenching with water on
completion was allowed to stir for 24 h. TLC analysis of
the reaction mixture revealed the presence of only one spot
corresponding to the product 5a.
Results and Discussion
The current study commenced with the synthesis of alde-
hydes 1 and 2 according to reported procedures.[1–2] Optimi-
zation studies were initiated by treating 1 with methyl acryl-
ate in the presence of DABCO under neat condition
(Scheme 1). This reaction smoothly affords the product 3a
in good yields. In order to generate the allyl bromide, 3a
was treated with PBr3 in dichloromethane at 0 °C. Al-
though the reaction was complete in 30 min, TLC analysis
revealed the presence of three spots out of which the most
non-polar spot displayed highly fluorescent green colour
under UV light (254 nm). Quenching the reaction mixture
with water followed by extraction furnished a residue which
displayed two spots on TLC instead of the initial three, thus
indicating either loss or transformation of one of the prod-
ucts into other during aqueous work up. However, purifica-
tion of the residue via column chromatography resulted in
a single product as solid which corresponded to the fluores-
cent spot of TLC. On the basis of this result we presumed
that either the polar fraction present in the product could
not be eluted, or it was also transformed during chromato-
Figure 3. Plausible mechanism for the formation of indolizino-in-
dole via allyl bromide.
1
graphic purification on silica gel. H- and 13C NMR analy-
sis of the isolated product revealed the presence of one CH2
signal instead of the expected two (one for the allyl chain
and other for the allyl bromide) and two extra CH signals
in the aromatic region. A HMBC spectrum coupled with
HRMS data led us to establish the structure of the product
as 5a instead of the anticipated allyl bromide. Perhaps the
reaction of PBr3 has started with the formation of allyl bro-
mide which could have undergone a nucleophilic attack by
the nitrogen of C-ring to form a salt that hydrates and re-
arranges in the presence of water to afford the isolated
In order to find out more about the general applicability
of this sequence we generated 3b–e, 4a,b by reaction of 1
and 2 with different activated alkenes. Treatment of 3b–e,
4a,b with PBr3 for 1–2 h followed by aqueous work up for
24 h resulted in the desired products 5b–e, 6a,b. In support
of the fact that the intramolecular cyclization reaction is
preceded by the formation of allyl bromide, during the reac-
tion of 4a with PBr3, crude 7 was separated and subjected
to 1H NMR and HRMS analysis (Scheme 1). Both data
confirm the presence of allyl bromide. Alternating the allyl
chain on the nitrogen of indole with propargyl and benzyl
groups furnish aldehydes 8 and 9, respectively, which were
then examined for similar reactions. Gratifyingly these sub-
strates too undergo the MBH reaction to afford 10a,d,e and
11a,b,d,e which after bromination yielded the desired prod-
ucts 12a,d,e and 13a,b,d,e, respectively (Scheme 2). These
results imply that the intramolecular cyclization is not influ-
enced by the substitution on the nitrogen of the indole sub-
unit.
In previous study with 2-pyridinecarboxaldehyde it has
been shown that acetylating the MBH adduct with acetic
anhydride leads to the formation of an indolizine deriva-
tive.[7] Therefore we decided to probe the effectiveness of
acetylation for intramolecular cyclization in compound 3.
Accordingly in a pilot study 3a was treated with acetyl chlo-
ride in the presence of pyridine in MeCN. After screening
for optimum conditions it was observed that the reaction
of 3a with 5 equiv. of acetyl chloride in the presence of
2 equiv. of pyridine in dry MeCN at 90 °C in 15 h yielded
5a in 54% yield (Scheme 3). On the other hand heating 3a
Scheme 1. Reagents and conditions: i. DABCO, room temp., 3 h–
15 d. ii. PBr3, 0 °C, 30 min–2 h then left in water for 16–24 h.
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V. Singh, S. Hutait, S. Batra
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with tert-butyl acrylate we could isolate adduct 16 in 86%
yields beside the indolizino-indole 15d (5%) as the minor
product. Nevertheless 16 upon treatment with PBr3 fur-
nished the required product 15d in 43% yield.
Scheme 2. Reagents and conditions i. DABCO, room temp., 4 h–
12 d. ii. PBr3, 0 °C, 30 min–2 h. then kept in water for 16–24 h.
with 5 equiv. of acetic anhydride in the presence of 2 equiv.
of pyridine at 80 °C for 16 h afforded the compound 5a in
46% yield.
Scheme 4. Reagents and conditions i. alkyl acrylate, DABCO, room
temp., 3–15 d. ii. PBr3, 0 °C, 1 h. then kept in water for 16 h.
The success of the strategy invoked us to investigate sim-
ilar reaction employing alkenones as the participating acti-
vated alkene. We anticipated that a successful MBH reac-
tion of cycloalkenone with different β-carboline-based alde-
hydes would lead to adducts which would react with PBr3
to yield the allyl bromide. The bromide would instantane-
ously undergo an intramolecular cyclization to afford a
product having similar framework as that of alkaloid
homofascaplysin. Accordingly, we examined the reaction of
1–2 and 9 with cyclohexenone and cyclopentenone under
the influence of DMAP in aqueous THF for 36 to 48 h.
Scheme 3. Reagents and conditions i. AcCl, Py, dry MeCN, 80 °C,
15 h. ii. Ac2O, Py, dry MeCN, 80 °C, 16 h.
Encouraged by results of the study, we next directed our Gratifyingly for all reactions the corresponding products
attention towards analogous N-substituted aldehyde origi- were furnished in 48–73% yields (Scheme 5). However, 17
nating from tryptamine. Accordingly, 14 was prepared and could not be isolated in pure form as it undergoes cycliza-
subjected to MBH reaction with different acrylates at room tion to afford 21 during purification via silica gel
temperature under neat conditions. As compared to reac- chromatography. Treatment of 17–20 with PBr3 expectedly
tions of aldehydes originating from tryptophan ester, reac- furnished the desired products 21–24. Encouraged by these
tions of 14 were found to be sluggish. But it was pleasing results, we then subjected 14 to reaction with cyclohexenone
to note that except for the reaction of tert-butyl acrylate, in in the presence of DMAP under aqueous condition for 4 d
all cases the isolated products were established to be the to provide 25 in a one-pot reaction in 58% yield
indolizino-indoles 15a–c (Scheme 4). For the reaction of 14 (Scheme 6).
Scheme 5. Reagents and conditions i. DMAP, THF/H2O (1:1), r.t., 36–48 h. ii. PBr3, 0 °C, 1 h, 30 min–1 h. then kept in water for 16 h.
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Synthesis of Indolizino-indole Derivatives
0.50 (hexane/EtOAc, 60:40) to obtain 3a as a white solid (0.534 g
from 0.43 g, 96%). For analytical grade was purified via silica gel
(60–120 mesh) column chromatography by hexane/EtOAc (70:30,
v/v) to afford 3a, m.p. 151–153 °C.
Methyl 9-Allyl-1-[1-hydroxy-2-(methoxycarbonyl)allyl]-9H-β-carb-
oline-3-carboxylate (3a): IR (KBr): ν
= 1722 (CO2CH3), 3422
˜
max
(OH) cm–1. 1H NMR (300 MHz, CDCl3): δ = 3.δ = 90 (s, 3 H,
CO2CH3), 4.02 (s, 3 H, CO2CH3), 4.80 (d, J = 17.2 Hz, 1 H,
=CHHallyl), 5.03 (td, J1 = 2.2, J2 = 18.3 Hz, 1 H, CHHN), 5.18 (d,
J = 8.6 Hz, 1 H, =CHHallyl), 5.25 (td, J1 = 2.2, J2 = 18.3 Hz,
1 H, CHHN), 5.26 (s, 1 H, CHOH), 5.46 (d, J = 8.6 Hz, 1 H,
=CHHadduct), 6.00–6.12 (m, 1 H, =CH), 6.21 (d, J = 8.6 Hz, 1 H,
=CHHadduct), 6.24 (s, 1 H, CHOH), 7.40 (t, J = 7.5 Hz, 1 H, ArH),
7.48 (d, J = 8.4 Hz, 1 H, ArH), 7.62–7.67 (m, 1 H, ArH), 8.23 (d,
J = 7.9 Hz, 1 H, ArH), 8.88 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3) δ = 47.2, 52.4, 52.6, 69.6, 110.5, 116.9, 117.6,
121.3, 121.6, 121.8, 126.6, 129.3, 130.4, 132.8, 135.3, 135.7, 142.1,
142.2, 166.2, 167.6 ppm. MS (ES): m/z (%) = 381.2 (100) [M + 1]
+, 403.2 (33) [M + 23]+. C21H20N2O5 (380.1372): calcd. C 66.31, H
5.30, N 7.36; found C 66.25, H 5.46, N 7.54.
Scheme 6. Reagents and conditions i. DMAP, THF/H2O (1:1), r.t.,
4 d.
Conclusions
In summary we have demonstrated a new application of
the MBH chemistry with N-substituted β-carboline-based
electrophiles to generate novel indolizino-indoles. These
products are the mimics of the alkaloids harmicine and
homofascaplysin. It was found that the presence of an elec-
tron-withdrawing substituent on the pyridine ring of 1-
formyl-β-carboline originating from tryptophan weakens
the nucleophilicity of the pyridine nitrogen. As a conse-
quence the cyclization occurs only after treatment of the
Methyl 11-Allyl-11H-indolizino[8,7-b]indole-2-carboxylate (15a):
The title compound was prepared following the above-described
general procedure. Purification by column chromatography
[EtOAc/hexane, 15:85, v/v, Rf = 0.50 (EtOAc/hexane, 20:80, v/v)]
MBH adduct with PBr3 or acetyl chloride (acetic an- gave a white solid (0.203 g from 0.25 g); yield 63%; m.p. 126–
128 °C. IR (KBr): ν
= 1712 (CO2CH3) cm–1. 1H NMR
˜
hydride), thus forming a more reactive allylic electrophile.
On the other hand, the 1-formyl-β-carboline originating
from tryptamine did not require any activation, cyclized de-
rivatives were furnished during the MBH reaction. The
strategy described herein highlights the usefulness of the
MBH adduct as valuable source for important structural
motifs.
max
(300 MHz, CDCl3): δ = 3.91 (s, 3 H, CO2CH3), 4.98 (d, J =
17.2 Hz, 1 H, =CHH), 5.19 (t, J = 4.7 Hz, 3 H, CH2N, =CHH),
6.09–6.21 (m, 1 H, =CH), 7.11 (s, 1 H, ArH), 7.26 (q, J = 5.4 Hz,
2 H, ArH), 7.34–7.44 (m, 2 H, ArH), 7.73 (d, J = 7.1 Hz, 1 H,
ArH), 7.91 (d, J = 7.8 Hz, 1 H, ArH), 7.95 (s, 1 H, ArH) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 46.8, 51.6, 98.6, 107.1, 109.6, 117.0,
118.2, 118.7, 119.0, 119.1, 120.5, 123.4, 123.8, 124.1, 130.5, 132.6,
138.8, 165.6 ppm. MS (ES): m/z (%) = 305.2 (100) [M + 1]+.
C19H16N2O2 (304.1212): calcd. C 74.98, H 5.30, N 9.20; found C
74.67, H 5.54, N 9.44.
Experimental Section
Ethyl 11-Allyl-11H-indolizino[8,7-b]indole-2-carboxylate (15b): The
title compound was prepared following the above-described general
procedure. Purification by column chromatography [EtOAc/hex-
ane, 15:85, v/v, Rf = 0.54 (EtOAc/hexane, 20:80, v/v)] gave a yellow
General: Melting points were determined in capillary tubes on a
Precision melting point apparatus containing silicon oil. IR spectra
were recorded using a Perkin–Elmer RX I FTIR spectrophotome-
ter. 1H NMR and 13C NMR spectra were recorded either on a
Bruker DPX-200 FT or Bruker Avance DRX-300 spectrometer,
using TMS as an internal standard (chemical shifts in δ). The
ESMS were recorded on MICROMASS Quadro-II LCMS system.
The HRMS spectra were recorded as EI-HRMS on a JEOL system
or as DART-HRMS (recorded as ES+) on a JEOL-AccuTOF
JMS-T100LC Mass spectrometer having a DART (Direct Analysis
in Real Time) source. Elemental analyses were performed on a
Carlo–Erba 108 or an Elementar Vario EL III microanalyzer. The
room temperature varied between 20 and 35 °C. The 13C NMR
spectra of fluoro-substituted derivatives display extra peaks due to
C,F couplings.
solid (0.068 g from 0.15 g); yield 48%; m.p. 128–129 °C. IR (KBr):
1
ν
= 1707 (CO2Et) cm–1. H NMR (300 MHz, CDCl3): δ = 1.41
˜
max
(t, J = 7.1 Hz, 3 H, OCH2CH3), 4.38 (q, J = 7.1 Hz, 2 H,
OCH2CH3), 4.97 (d, J = 16.4 Hz, 1 H, =CHH), 5.19 (d, J = 4.8 Hz,
3 H, CH2N and =CHH), 6.09–6.21 (m, 1 H, =CH), 7.11 (s, 1 H,
ArH), 7.23–7.29 (m, 2 H, ArH), 7.35–7.44 (m, 2 H, ArH), 7.73 (d,
J = 7.0 Hz, 1 H, ArH), 7.91 (d, J = 7.8 Hz, 1 H, ArH), 7.95 (d, J
= 1.2 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 14.6,
46.8, 60.3, 98.6, 107.1, 109.6, 109.8, 117.0, 118.2, 119.0, 119.1,
120.5, 123.4, 123.8, 124.1, 125.6, 130.5, 132.7, 138.8 ppm. MS (ES):
m/z (%) = 305.2 (100) [M + 1]+. DART-HRMS (ES+): calcd. for
C20H18N2O2 319.1436; found 319.1446.
General Procedure for the Synthesis of 3b–e, 4a,b, 10a,d,e, 11a,b,d,e,
15a–c and 16, Exemplified for 3a: To a mixture of 1 (0.43 g, Butyl 11-Allyl-11H-indolizino[8,7-b]indole-2-carboxylate (15c): The
1.69 mmol) and DABCO (0.19 g, 1.69 mmol), methyl acrylate title compound was prepared following the above-described general
(1.53 mL, 16.93 mmol) was added. The mixture was stirred at room procedure. Purification by column chromatography [EtOAc/hex-
temperature for 3 d. After completion of the reaction as monitored
by TLC, the content was poured into water (50 mL) and EtOAc
(50 mL) was added. The organic layer was partitioned and the
aqueous layer was further extracted with EtOAc (3ϫ25 mL). The
pooled organic layer was washed with brine (40 mL), dried with
anhydrous Na2SO4 and evaporated to yield a solid residue which
was further purified by triturating with hexane/EtOAc, 95:05; Rf =
ane, 08:92, v/v, Rf = 0.75 (EtOAc/hexane, 20:80, v/v)] gave a yellow
oil (0.126 g from 0.20 g); yield 43%. IR (neat): ν = 1705
˜
max
(CO2CH2CH2CH2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.00 (t, J = 7.3 Hz, 3 H, CO2CH2CH2CH2CH3), 1.44–1.54 (m, 2 H,
CO2CH2CH2CH2CH3), 1.72–1.82 (m, 2 H, CO2CH2CH2CH2CH3),
4.33 (t, J = 6.7 Hz, 2 H, CO2CH2CH2CH2CH3), 4.98 (d, J =
16.4 Hz, 1 H, =CHH), 5.18–5.22 (m, 3 H, =CHH and CH2N),
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V. Singh, S. Hutait, S. Batra
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6.09–6.21 (m, 1 H, =CH), 7.11 (s, 1 H, ArH), 7.22–7.30 (m, 2 H,
2 H, CO2CH2CH2CH2CH3), 4.99 (d, J = 17.2 Hz, 1 H, =CHH),
ArH), 7.34–7.40 (m, 1 H, ArH), 7.42 (d, J = 8.0 Hz, 1 H, ArH), 5.19 (s, 2 H, CH2N), 5.22 (d, J = 17.2 Hz, 1 H, =CHH), 6.08–6.20
7.73 (d, J = 6.7 Hz, 1 H, ArH), 7.90 (d, J = 7.7 Hz, 1 H, ArH),
7.94 (d, J = 1.4 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 14.0, 19.4, 29.8, 31.0, 46.9, 64.3, 98.7, 107.1, 109.6, 109.8, 117.0,
118.1, 119.0, 119.1, 120.5, 123.3, 123.8, 124.1, 130.6, 132.6, 138.7,
165.3 ppm. MS (ES): m/z (%) = 347.2 (100) [M + 1]+. C22H22N2O2
(346.1681): calcd. C 76.28, H 6.40, N 8.09; found C 76.45, H 6.38,
N 7.98.
(m, 1 H, =CH), 7.31–7.36 (m, 2 H, ArH), 7.43 (d, J = 2.4 Hz, 2
H, ArH), 7.96 (d, J = 7.7 Hz, 1 H, ArH), 8.40 (s, 1 H, ArH), 9.40
(s, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 14.0, 19.5,
31.1, 46.9, 52.3, 64.4, 100.8, 109.0, 109.8, 116.4, 117.4, 117.9, 119.2,
119.5, 121.4, 121.5, 123.6, 124.0, 124.6, 131.9, 133.8, 139.6, 163.2,
165.2 ppm. MS (ES): m/z (%) = 405.2 (100) [M + 1]+. DART-
HRMS (ES+): calcd. C24H25N2O4: 405.1814; found 405.1804.
General Procedure for the Synthesis of 5b–e, 6a,b, 12a,d,e, 13a,b,d,e,
15d and 21–24, Exemplified for 5a: To a solution of 3a (0.13 g,
0.34 mmol) in dry dichloromethane (6 mL), PBr3 (0.07 mL,
0.68 mmol) was added and the reaction was stirred at 0 °C for
30 min. After completion, the content was poured into crushed ice
and left for 16 h. Thereafter, the mixture was neutralized with
NaHCO3. The organic layer was separated and the aqueous layer
2-(tert-Butyl) 5-Methyl 11-Allyl-11H-indolizino[8,7-b]indole-2,5-di-
carboxylate (5d): The title compound was prepared following the
above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 10:90, Rf = 0.58 (EtOAc/hexane,
10:90, v/v)] gave a yellow solid (0.11 g from 0.20 g); yield 58%;
m.p. 98–100 °C. IR (KBr): νmax = 1708 (CO2C4H9) cm–1. 1H NMR
˜
(300 MHz, CDCl3) δ = 1.63 (s, 9 H, CO2C4H9), 4.03 (s, 3 H,
was further extracted with CHCl3 (3ϫ25 mL). The organic layers CO2CH3), 5.00 (d, J = 17.2 Hz, 1 H, =CHH), 5.18–5.25 (m, 3 H,
were combined and washed with brine (50 mL), dried with anhy- CH2N and = CHH), 6.08–6.20 (m, 1 H, =CH), 7.29 (d, J = 1.4 Hz,
drous Na2SO4 and concentrated to yield a crude product which
was further purified via silica gel (60–120 mesh) column
chromatography by [hexane/EtOAc, 90:10, Rf = 0.60 (hexane/
EtOAc, 80:20, v/v)] to yield 5a as a yellow solid (with green tinge)
(0.092 g from 0.13 g); yield 74%; m.p. 146–148 °C.
1 H, ArH), 7.30–7.35 (m, 1 H, ArH), 7.43 (d, J = 7.7 Hz, 2 H,
ArH), 7.96 (d, J = 7.7 Hz, 1 H, ArH), 8.40 (s, 1 H, ArH), 9.35 (s,
1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 28.6, 46.9, 52.3,
80.6, 100.9, 108.9, 109.8, 116.4, 117.5, 117.9, 119.2, 121.2, 121.4,
123.7, 123.9, 124.6, 134.0, 133.9, 139.5, 163.3, 164.7 ppm. MS (ES):
m/z (%) = 405.1 (100) [M + 1]+. DART-HRMS (ES+): calcd.
C24H25N2O4: 405.1794; found 405.1814.
Dimethyl
11-Allyl-11H-indolizino[8,7-b]indole-2,5-dicarboxylate
(5a): IR (KBr): νmax = 1704 (CO2CH3) cm–1. 1H NMR (300 MHz,
˜
CDCl3) δ = 3.90 (s, 3 H, CO2CH3), 3.96 (s, 3 H, CO2CH3), 4.92 Methyl 11-Allyl-2-cyano-11H-indolizino[8,7-b]indole-5-carboxylate
(d, J = 17.2 Hz, 1 H, =CHH), 5.00 (t, J = 2.9 Hz, 2 H, CH2N), (5e): The title compound was prepared following the above-de-
5.18 (d, J = 10.4 Hz, 1 H, =CHH), 6.01–6.13 (m, 1 H, =CH), 7.17
(d, J = 1.4 Hz, 1 H, ArHpyrrole), 7.25–7.41 (m, 3 H, ArH), 7.87 (d,
scribed general procedure. Purification by column chromatography
[EtOAc/hexane, 10:90, Rf = 0.55 (EtOAc/hexane, 10:90, v/v)] gave
J = 7.7 Hz, 1 H, ArH), 8.21 (s, 1 H, ArH), 9.31 (d, J = 1.4 Hz, 1 a light yellow solid with a green tinge (0.183 g from 0.44 g); yield
H, ArHpyrrole) ppm. 13C NMR (50 MHz, CDCl3) δ = 46.8, 51.6, 44%; m.p. 183–185 °C. IR (KBr): ν
= 1697 (CO2CH3), 2223
˜
max
52.3, 100.7, 109.0, 109.8, 116.4, 117.4, 117.8, 119.0, 119.2, 121.5,
123.6, 124.0, 124.6, 131.9, 133.7, 139.5, 163.1, 165.5 ppm. MS (ES):
m/z (%) = 363.2 (100) [M + 1]+. DART-HRMS (ES+): calcd.
C21H19N2O4 363.1345; found 363.1331.
(CN) cm–1. 1H NMR (300 MHz, CDCl3) δ = 4.03 (s, 3 H,
CO2CH3), 4.97 (d, J = 17.2 Hz, 1 H, =CHH), 5.14 (t, J = 1.4 Hz,
2 H, CH2N), 5.26 (d, J = 10.5 Hz, 1 H, =CHH), 6.06–6.19 (m, 1
H, =CH), 7.10 (d, J = 1.4 Hz, 1 H, ArH), 7.34–7.39 (m, 1 H, ArH),
7.47 (d, J = 3.7 Hz, 2 H, ArH), 7.99 (d, J = 7.8 Hz, 1 H, ArH),
8.45 (s, 1 H, ArH), 9.36 (s, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 46.9, 52.5, 96.9, 102.2, 109.8, 109.9, 116.5, 116.7,
117.7, 119.4, 121.8, 123.2, 123.3, 124.0, 125.3, 131.5, 132.8, 133.5,
139.6, 162.9 ppm. MS (ES): m/z (%) = 330.1 (100) [M + 1]+.
C20H15N3O2 (329.1164): calcd. C 72.94, H 4.59, N 12.76; found C
73.09, H 4.73, N 12.54.
2-Ethyl 5-Methyl 11-Allyl-11H-indolizino[8,7-b]indole-2,5-dicarb-
oxylate (5b): The title compound was prepared following the above-
described general procedure. Purification by triturating [EtOAc/
hexane, 05:95, Rf = 0.62 (EtOAc/hexane, 20:80, v/v)] gave a yellow
solid with a green tinge (0.094 g from 0.21 g); yield 45%; m.p. 160–
161 °C. IR (KBr): ν
= 1704 (CO2CH3 and CO2CH2CH3) cm–1.
˜
max
1H NMR (300 MHz, CDCl3) δ = 1.42 (t, J = 7.1 Hz, 3 H,
CO2CH2CH3), 4.03 (s, 3 H, CO2CH3), 4.40 (q, J = 7.1 Hz, 2 H,
Dimethyl 11-Allyl-8-fluoro-11H-indolizino[8,7-b]indole-2,5-dicarb-
CO2CH2CH3), 4.99 (d, J = 17.2 Hz, 1 H, =CHH), 5.19–5.25 (s, 3 oxylate (6a): The title compound was prepared following the above-
H, CH2N and = CHH), 6.09–6.21 (m, 1 H, =CH), 7.31–7.36 (m, 2
H, ArH), 7.43 (t, J = 2.6 Hz, 2 H, ArH), 7.96 (d, J = 7.7 Hz, 1 H,
described general procedure. Purification by column chromatog-
raphy [EtOAc/hexane, 20:80, v/v, Rf = 0.60 (EtOAc/hexane, 30:70,
v/v)] gave a yellow solid (0.421 g from 0.70 g); yield 63%; m.p. 195–
ArH), 8.40 (s, 1 H, ArH), 9.41 (d, J = 1.2 Hz, 1 H, ArH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 14.6, 46.8, 52.2, 60.4, 100.7, 108.9,
109.8, 116.3, 117.4, 117.8, 119.1, 119.4, 121.4, 123.5, 124.0, 124.6,
131.9, 133.7, 139.5, 163.2, 165.1 ppm. MS (ES): m/z (%) = 377.2
(100) [M + 1]+. C22H20N2O4 (376.1423): calcd. C 78.15, H 6.89, N
4.56; found C 78.10, H 6.81, N 4.46.
197 °C. IR (KBr): ν
= 1713 (CO2CH3) cm–1. 1H NMR
˜
max
(300 MHz, CDCl3): δ = 3.93 (s, 3 H, CO2CH3), 4.03 (s, 3 H,
CO2CH3), 4.94 (d, J = 17.0 Hz, 1 H, =CHH), 5.15–5.18 (s, 2 H,
CH2N), 5.24 (d, J = 10.3 Hz, 1 H, =CHH), 6.08–6.20 (m, 1 H,
=CH), 7.11–7.18 (m, 1 H, ArH), 7.30 (d, J = 1.4 Hz, 1 H, ArH),
7.33–7.37 (m, 1 H, ArH), 7.61 (dd, J1 = 2.4, J2 = 8.8 Hz, 1 H,
2-Butyl 5-Methyl 11-Allyl-11H-indolizino[8,7-b]indole-2,5-dicarb-
oxylate (5c): The title compound was prepared following the above-
described general procedure. Purification by column chromatog-
raphy [EtOAc/hexane, 10:90, Rf = 0.55 (EtOAc/hexane, 10:90,
v/v)] gave a light yellow solid with a green tinge (0.35 g from
ArH), 8.33 (s, 1 H, ArH), 9.42 (d, J = 1.4 Hz, 1 H, ArH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 47.1, 51.6, 52.4, 101.1, 104.6, 105.0,
108.6, 108.7, 110.5, 110.7, 112.4, 112.7, 116.2, 117.6, 118.0, 119.2,
121.8, 123.8, 124.1, 124.2, 131.7, 134.7, 135.9, 157.3, 160.5, 163.0,
165.4 ppm. MS (ES): m/z (%) = 381.1 (100) [M + 1]+. DART-
HRMS (ES+): calcd. C21H18FN2O4 381.1251; found 381.1232.
0.50 g); yield 73%; m.p. 161–163 °C. IR (KBr): ν
= 1707
˜
max
(CO2CH2CH2CH2CH3) cm–1. 1H NMR (300 MHz, CDCl3) δ =
1.00 (t, J = 7.3 Hz, 3 H, CO2CH2CH2CH2CH3), 1.53 (q, J =
3-Ethyl 5-Methyl 11-Allyl-8-fluoro-11H-indolizino[8,7-b]indole-2,5-
7.4 Hz, 2 H, CO2CH2CH2CH2CH3), 1.77 (q, J = 6.8 Hz, 2 H, dicarboxylate (6b): The title compound was prepared following the
CO2CH2CH2CH2CH3), 4.03 (s, 3 H, CO2CH3), 4.35 (t, J = 6.7 Hz, above-described general procedure. Purification by column
3688
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3684–3691

Synthesis of Indolizino-indole Derivatives
chromatography [EtOAc/hexane, 20:80, v/v, Rf = 0.65 (EtOAc/hex-
ane, 30:70, v/v)] gave a yellow solid with a green tinge (0.20 g from
Dimethyl 11-Benzyl-11H-indolizino[8,7-b]indole-2,5-dicarboxylate
(13a): The title compound was prepared following the above-de-
scribed general procedure. Purification by column chromatography
0.50 g); yield 41%; m.p. 168–170 °C. IR (KBr): ν
= 1709
˜
max
(CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 1.42 (t, J = [EtOAc/hexane, 15:85, v/v, Rf = 0.50 (EtOAc/hexane, 25:75, v/v)]
7.1 Hz, 3 H, CO2CH2CH3), 4.02 (s, 3 H, CO2CH3), 4.40 (q, J = gave a yellow solid (0.23 g from 0.40 g); yield 59%; m.p. 209–
7.1 Hz, 2 H, CO2CH2CH3), 4.97 (d, J = 17.1 Hz, 1 H, =CHH), 211 °C. IR (KBr): ν
= 1713 (CO2CH3) cm–1. 1H NMR
˜
max
5.16 (d, J = 2.0 Hz, 2 H, CH2N), 5.24 (d, J = 10.4 Hz, 1 H,
(300 MHz, CDCl3): δ = 3.88 (s, 3 H, CO2CH3), 4.04 (s, 3 H,
=CHH), 6.08–6.17 (m, 1 H, =CH), 7.11–7.17 (m, 1 H, ArH), 7.30– CO2CH3), 5.81 (s, 2 H, CH2N), 7.15 (t, J = 6.3 Hz, 2 H, ArH),
7.36 (m, 2 H, ArH), 7.59 (dd, J1 = 2.1, J2 = 8.8 Hz, 1 H, ArH),
8.30 (s, 1 H, ArH), 9.40 (s, 1 H, ArH) ppm. 13C NMR (75 MHz,
CDCl3): δ = 14.6, 47.1, 52.3, 60.5, 101.1, 104.6, 104.9, 108.6, 108.7,
110.5, 110.7, 112.3, 112.7, 116.1, 117.6, 118.0, 119.6, 121.7, 123.8,
124.1, 124.3, 131.7, 134.7, 135.9, 157.3, 160.5, 163.1, 165.0 ppm.
7.22–7.32 (m, 1 H, ArH), 7.33–7.36 (m, 3 H, ArH), 7.36–7.40 (m,
3 H, ArH), 7.99 (d, J = 6.7 Hz, 1 H, ArH), 8.45 (s, 1 H, ArH),
9.41 (d, J = 1.3 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3):
δ = 29.8, 48.4, 51.6, 52.4, 100.7, 109.3, 110.2, 116.5, 118.2, 119.2,
119.3, 121.6, 121.7, 123.8, 124.2, 124.8, 126.3, 127.9, 129.2, 134.1,
MS (ES): m/z (%) = 395.2 (100) [M + 1]+. DART-HRMS (ES+): 136.2, 139.9, 163.2, 165.5 ppm. MS (ES): m/z (%) = 413.2 (100) [M
calcd. C22H20FN2O4: C, 395.1381; found 395.1377.
+ 1]+. C25H20N2O4 (412.1423): calcd. C 72.80, H 4.89, N 6.79;
found C 72.96, H 4.78, N 6.83.
Dimethyl 11-(Prop-2-ynyl)-11H-indolizino[8,7-b]indole-2,5-dicarb-
oxylate (12a): The title compound was prepared following the
above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 15:85, v/v, Rf = 0.40 (EtOAc/hex-
ane, 30:70, v/v)] gave a yellow solid with a green tinge (0.134 g
2-Ethyl 5-Methyl 11-Benzyl-11H-indolizino[8,7-b]indole-2,5-dicarb-
oxylate (13b): The title compound was prepared following the
above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 15:85, v/v, Rf = 0.52 (EtOAc/hex-
ane, 20:80, v/v)] gave a yellow solid with a green tinge (0.346 g
from 0.30 g); yield 47%; m.p. 242–244 °C. IR (KBr): ν
= 1712
˜
max
(CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.39 (d, J =
2.6 Hz, 1 H, CCH), 3.94 (d, J = 3.4 Hz, 3 H, CO2CH3), 4.03 (d, J
= 3.4 Hz, 3 H, CO2CH3), 5.31 (d, J = 2.8 Hz, 2 H, CH2N), 7.33–
7.39 (m, 1 H, ArH), 7.44–7.57 (m, 3 H, ArH), 7.96 (q, J = 3.8 Hz,
1 H, ArH), 8.38 (d, J = 3.5 Hz, 1 H, ArH), 9.43 (dd, J1 = 1.3, J2
= 3.4 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 39.3,
56.7, 57.6, 81.3, 84.4, 106.2, 114.1, 115.6, 121.6, 122.9, 123.8, 124.9,
125.6, 126.9, 128.1, 128.8, 130.1, 137.8, 144.0, 167.9, 169.5 ppm.
MS (ES): m/z (%) = 361.2 (100) [M + 1]+. C21H16N2O4 (360.1110):
calcd. C 69.99, H 4.48, N 7.77; found C 70.30, H 4.54, N 7.56.
from 0.80 g); yield 45%; m.p. 185–187 °C. IR (KBr): ν
= 1710
˜
max
(CO2CH2CH3 and CO2CH3) cm–1. H NMR (300 MHz, CDCl3):
δ = 1.36 (t, J = 7.1 Hz, 3 H, OCH2CH3), 4.06 (s, 3 H, CO2CH3),
4.34 (q, J = 7.1 Hz, 2 H, OCH2CH3), 5.82 (s, 2 H, CH2), 7.14 (d,
J = 6.3 Hz, 2 H, ArH), 7.23–7.33 (m, 4 H, ArH), 7.35–7.42 (m, 3
H, ArH), 7.99 (d, J = 6.7 Hz, 1 H, ArH), 8.44 (s, 1 H, ArH), 9.40
(d, J = 1.4 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ =
14.6, 48.3, 52.3, 60.4, 109.2, 110.1, 116.4, 118.1, 119.2, 119.6, 121.5,
121.7, 123.8, 124.1, 124.8, 126.3, 127.9, 129.2, 134.1, 136.2, 139.9,
163.2, 165.0 ppm. MS (ES): m/z (%) = 427.2 (100) [M + 1]+.
C26H22N2O4 (426.1580): calcd. C 73.23, H 5.20, N 6.57; found C
73.47, H 5.04, N 6.69.
1
2-tert-Butyl 5-Methyl 11-(Prop-2-ynyl)-11H-indolizino[8,7-b]indole-
2,5-dicarboxylate (12d): The title compound was prepared follow-
ing the above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 15:85, v/v, Rf = 0.50 (EtOAc/hex-
ane, 20:80, v/v)] gave a yellowish solid with a green tinge (0.143 g
2-(tert-Butyl) 5-Methyl 11-Benzyl-11H-indolizino[8,7-b]indole-2,5-
dicarboxylate (13d): The title compound was prepared following
the above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 15:85, v/v, Rf = 0.80 (EtOac/hex-
ane, 20:80, v/v)] gave a yellow solid with a green tinge (0.452 g
from 0.30 g); yield 50%; m.p. 201–203 °C. IR (KBr): ν
= 1708
˜
max
(CO2CC3H9) cm–1. H NMR (300 MHz, CDCl3): δ = 1.64 (s, 9 H,
CO2CC3H9), 2.39 (t, J = 2.4 Hz, 1 H, CCH), 4.02 (s, 3 H,
CO2CH3), 5.29 (d, J = 2.5 Hz, 2 H, CH2N), 7.32–7.37 (m, 1 H,
ArH), 7.43–7.48 (m, 2 H, ArH), 7.54 (d, J = 8.2 Hz, 1 H, ArH),
7.94 (d, J = 7.7 Hz, 1 H, ArH), 8.35 (s, 1 H, ArH), 9.33 (d, J =
1.4 Hz, 1 H, ArH) ppm. 13C NMR (50 MHz, CDCl3): δ = 28.6,
34.2, 52.3, 74.1, 80.6, 100.9, 109.1, 109.5, 115.9, 118.1, 119.2, 121.2,
121.4, 123.6, 123.7, 124.7, 133.3, 138.8, 163.1, 164.5 ppm. MS (ES):
m/z (%) = 403.1 (100) [M + 1]+. DART-HRMS (ES+): calcd.
C24H23N2O4 403.1658; found 403.1644.
1
from 1.00 g); yield 47%; m.p. 179–181 °C. IR (KBr): ν
= 1707
˜
max
(CO2CC3H9 and CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ
= 1.59 (s, 9 H, CO2CC3H9), 4.03 (d, J = 1.9 Hz, 3 H, CO2CH3),
5.81 (s, 2 H, CH2N), 7.16 (t, J = 8.4 Hz, 3 H, ArH), 7.26–7.33 (m,
3 H, ArH), 7.34–7.40 (m, 3 H, ArH), 7.99 (d, J = 6.7 Hz, 1 H,
ArH), 8.43 (t, J = 6.7 Hz, 1 H, ArH), 9.30 (d, J = 0.9 Hz, 1 H,
ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 28.6, 48.3, 52.3, 80.5,
100.9, 109.1, 110.1, 116.3, 118.0, 119.2, 121.2, 123.7, 123.9, 124.7,
126.2, 127.8, 129.1, 134.1, 136.2, 139.9, 163.3, 164.5 ppm. MS (ES):
m/z (%) = 455.1 (100) [M + 1]+. DART-HRMS (ES+): calcd.
C28H27N2O4 454.1971; found 454.1959.
1
Methyl 2-Cyano-11-(prop-2-ynyl)-11H-indolizino[8,7-b]indole-5-carb-
oxylate (12e): The title compound was prepared following the
above-described general procedure. Purification by column
chromatography [EtOAc/hexane, 25:75, v/v, Rf = 0.42 (EtOAc/hex-
ane, 20:80, v/v)] gave a white solid (0.144 g from 0.30 g); yield 51%;
Methyl 11-Benzyl-2-cyano-11H-indolizino[8,7-b]indole-5-carboxyl-
ate (13e): The title compound was prepared following the above-
described general procedure. Purification by column chromatog-
m.p. 212–214 °C. IR (KBr): ν
= 1724 (CO2CH3), 2224 (CN)
˜
max
cm–1. H NMR (300 MHz, CDCl3): δ = 2.44 (t, J = 2.4 Hz, 1 H, raphy [EtOAc/hexane, 10:90, v/v, Rf = 0.60 (EtOAc/hexane, 10:90,
1
CCH), 4.04 (s, 3 H, CO2CH3), 5.25 (d, J = 2.5 Hz, 2 H, CH2N), v/v)] gave a white solid with a green tinge (0.071 g from 0.17 g);
7.34 (s, 1 H, ArH), 7.36–7.42 (m, 1 H, ArH), 7.49–7.58 (m, 2 H,
ArH), 7.98 (d, J = 7.8 Hz, 1 H, ArH), 8.43 (s, 1 H, ArH), 9.39 (d,
J
DMSO): δ = 29.4, 53.0, 76.6, 79.0, 96.5, 103.6, 110.0, 111.0, 117.2,
118.0, 119.6, 120.3, 122.3, 123.1, 123.9, 125.6, 132.2, 134.8, 139.2,
162.8 ppm. MS (ES): m/z (%) = 328.1 (100) [M + 1]+. C20H13N3O2
(327.1008): calcd. C 73.38, H 4.00, N 12.84; found C 73.44, H 4.23,
N 12.78.
yield 43%; m.p. 227–229 °C. IR (KBr): ν
= 1707 (CO2CH3),
˜
max
2231 (CN) cm–1. 1H NMR (300 MHz, CDCl3): δ = 4.04 (s, 3 H,
CO2CH3), 5.76 (s, 2 H, CH2N), 6.94 (d, J = 0.8 Hz, 1 H, ArH),
7.08–7.11 (m, 2 H, ArH), 7.26–7.33 (m, 3 H, ArH), 7.36–7.41 (m,
1 H, ArH), 7.45 (t, J = 2.5 Hz, 2 H, ArH), 8.02 (d, J = 7.5 Hz, 1
H, ArH), 8.48 (s, 1 H, ArH), 9.33 (d, J = 1.4 Hz, 1 H, ArH) ppm.
13C NMR (50 MHz, CDCl3): δ = 29.8, 48.3, 52.6, 97.0, 102.3,
110.0, 110.1, 116.7, 117.9, 119.5, 122.0, 123.4, 124.0, 125.5, 125.9,
= 1.4 Hz, 1
H, ArH) ppm. 13C NMR (50 MHz, [D6]-
Eur. J. Org. Chem. 2010, 3684–3691
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3689

V. Singh, S. Hutait, S. Batra
FULL PAPER
128.1, 129.4, 135.8, 140.1, 162.9 ppm. MS (ES): m/z (%) = 380.1
(100) [M + 1]+. C24H17N3O2 (379.1321): calcd. C 75.97, H 4.52, N
11.08; found C 75.88, H 4.64, N 10.94.
H, CH2N), 7.11 (d, J = 7.0 Hz, 2 H, ArH), 7.23–7.30 (m, 4 H,
ArH), 7.33–7.40 (m, 3 H, ArH), 7.97 (d, J = 6.8 Hz, 1 H, ArH),
8.13 (d, J = 1.5 Hz, 1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3):
δ = 25.0, 26.6, 38.4, 48.4, 52.6, 97.0, 109.0, 110.2, 117.0, 119.2,
120.0, 121.6, 123.7, 123.8, 124.7, 124.9, 126.2, 127.8. 129.1, 133.9,
136.1, 138.4, 139.8, 163.5, 196.2 ppm. MS (ES): m/z (%) = 423.3
(100) [M + 1]+. DART-HRMS (ES+): calcd. C27H23N2O3 423.1709;
found 423.1689.
tert-Butyl 11-Allyl-11H-indolizino[8,7-b]indole-2-carboxylate (15d):
The title compound was prepared following the above-described
general procedure. Purification by column chromatography
[EtOAc/hexane, 10:90, v/v, Rf = 0.60 (EtOAc/hexane, 10:90, v/v)]
was obtained as a yellow oil (0.128 g from 0.30 g); yield 45%. IR
(neat): ν
= 1701 (CO2CC3H9) cm–1. 1H NMR (300 MHz, Methyl 12-Benzyl-1-oxo-2,3,4,12-tetrahydro-1H-benzo[2,3]indoliz-
˜
max
CDCl3): δ = 1.62 (s, 9 H, CO2CC3H9), 4.99 (d, J = 17.5 Hz, 1 H, ino[8,7-b]indole-6-carboxylate (24): The title compound was pre-
=CHH), 5.19 (t, J = 7.4 Hz, 3 H, CH2N and =CHH), 6.07–6.19
(m, 1 H, =CH), 7.06 (s, 1 H, ArH), 7.19–7.28 (m, 2 H, ArH), 7.33–
pared following the above-described general procedure. Purification
by column chromatography [EtOAc/hexane, 25:75, v/v, Rf = 0.60
7.43 (m, 2 H, ArH), 7.70 (d, J = 7.1 Hz, 1 H, ArH), 7.86 (d, J = (EtOAc/hexane, 50:50, v/v)] was obtained as a yellow solid (0.098 g
1.3 Hz, 1 H, ArH), 7.89 (d, J = 7.8 Hz, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 28.5, 46.8, 80.4, 98.7, 106.9, 109.5, 109.7,
117.0, 118.0, 119.0, 119.1, 120.4, 120.8, 123.4, 123.7, 123.9, 130.6,
132.7, 138.7, 164.6 ppm. MS (ES): m/z (%) = 347.1 (100) [M + 1]
+. DART-HRMS (ES+): calcd. C22H23N2O2 347.1760; found
347.1744.
from 0.20 g); y ield: 51%; m.p. Ͼ250 °C. IR (KBr): ν
= 1703
˜
max
(CO2CH3), 1711 (CO) cm–1. 1H NMR (300 MHz, CDCl3): δ =
2.95–2.99 (m, 2 H, CH2), 3.34–3.37 (m, 2 H, CH2), 4.03 (s, 3 H,
CO2CH3), 5.79 (s, 2 H, CH2N), 6.90 (s, 1 H, ArH), 7.09 (t, J =
3.4 Hz, 2 H, ArH), 7.24–7.28 (m, 4 H, ArH), 7.34–7.42 (m, 2 H,
ArH), 7.99 (d, J = 7.0 Hz, 1 H, ArH), 8.22 (s, 1 H, ArH) ppm. 13
C
NMR (50 MHz, CDCl3): δ = 25.7, 41.4, 48.2, 52.6, 93.1, 109.3,
110.1, 116.2, 119.3, 119.8, 121.8, 123.5, 125.0, 125.9, 127.9, 129.2,
130.6, 130.9, 134.0, 136.0, 140.0, 153.0, 162.7 ppm. MS (ES): m/z
(%) = 409.3 (100) [M + 1]+. C26H20N2O3 (408.1474): calcd. C 76.45,
H 4.94, N 6.86; found C 76.81, H 5.06, N 6.73.
Methyl 12-Allyl-1-oxo-2,3,4,12-tetrahydro-1H-benzo[2,3]indolizino-
[8,7-b]indole-6-carboxylate (21): The title compound was prepared
following the above-described general procedure. Purification by
column chromatography [EtOAc/hexane, 20:80, v/v, Rf = 0.40
(EtOAc/hexane, 50:50, v/v)] gave a white solid (0.576 g from 0.70 g);
yield 65%; m.p. 228–230 °C. IR (KBr): ν
= 1670 (CO), 1718
General Procedure for the Synthesis of 17–18, 20, 25, Exemplified
˜
max
(CO2CH3) cm–1. 1H NMR (300 MHz, CDCl3): δ = 2.20 (q, J = for 19: To a solution of 9 (0.50 g, 1.45 mmol) was added DMAP
6.3 Hz, 2 H, CH2), 2.65 (t, J = 5.8 Hz, 2 H, CH2), 2.86 (t, J =
6.0 Hz, 2 H, CH2), 4.04 (s, 3 H, CO2CH3), 4.95 (d, J = 17.0 Hz, 1
H, =CHH), 5.21 (t, J = 5.0 Hz, 3 H, =CHH and CH2N), 6.08–
6.20 (m, 1 H, =CH), 7.30–7.35 (m, 2 H, ArH), 7.39–7.46 (m, 2 H,
(0.071 g, 0.58 mmol) and cyclohexenone (2.66 mL, 29.5 mmol) in a
THF/water mixture (10 mL, 1:1, v/v). The reaction mixture was
stirred at room temperature for 48 h. After completion of the reac-
tion as monitored by TLC, the content was extracted with EtOAc
(3ϫ40 mL). The organic layer was washed with brine (70 mL),
dried with anhydrous Na2SO4 and evaporated to yield a solid resi-
due which was further purified via silica gel column chromatog-
raphy using [hexane/EtOAc, 40:60, Rf = 0.50 (hexane/EtOAc,
50:50)] to obtain 19 as a yellow solid (0.344 g from 0.50 g); yield
54%; m.p. 185–187 °C.
ArH), 7.94 (d, J = 7.7 Hz, 1 H, ArH), 8.10 (s, 1 H, ArH) ppm. 13
C
NMR (75 MHz, CDCl3): δ = 25.0, 26.6, 38.4, 46.9, 52.6, 97.0,
108.8, 109.9, 117.0, 117.3, 119.2, 119.8, 121.4, 123.6, 123.7, 124.6,
124.8, 131.9, 133.7, 138.4, 139.5, 163.5, 196.4 ppm. MS (ES): m/z
(%)
= 373.2 (100) [M +
1]+. DART-HRMS (ES+): calcd.
C23H21N2O3 373.1552; found 373.1534.
Methyl 12-Allyl-9-fluoro-1-oxo-2,3,4,12-tetrahydro-1H-benzo[2,3]-
indolizino[8,7-b]indole-6-carboxylate (22): The title compound was
prepared following the above-described general procedure. Purifi-
cation by column chromatography [EtOAc/hexane, 30:70, v/v, Rf =
0.38 (EtOAc/hexane, 50:50, v/v)] gave a white solid (0.06 g from
Methyl
9-Benzyl-1-[hydroxy(6-oxocyclohex-1-en-1-yl)methyl]-β-
= 1665 (CO), 1701
carboline-3-carboxylate (19): IR (KBr): ν
˜
max
(CO2CH3), 3448 (OH) cm–1. 1H NMR (300 MHz, CDCl3): δ =
1.57–1.63 (m, 1 H, CHH), 1.85–1.96 (m, 2 H, CH2), 2.04–2.14 (m,
2 H, CH2), 2.44–2.50 (m, 1 H, CHH), 4.03 (s, 3 H, CO2CH3), 5.64
(d, J = 18.0 Hz, 2 H, =CH and CHOH), 5.87 (d, J = 18.0 Hz, 1
0.15 g); yield 42%; m.p. Ͼ250 °C. IR (KBr): ν
= 1655 (CO),
˜
max
1
1713 (CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ = 2.18 (t, J H, CHOH), 6.27 (t, J = 4.2 Hz, 2 H, CH2Ph), 6.79 (t, J = 4.2 Hz,
= 6.2 Hz, 2 H, CH2), 2.68 (t, J = 6.3 Hz, 2 H, CH2), 2.87 (t, J = 2 H, ArH), 7.20–7.24 (m, 3 H, ArH), 7.33 (d, J = 8.3 Hz, 1 H,
6.1 Hz, 2 H, CH2), 4.03 (s, 3 H, CO2CH3), 4.92 (d, J = 17.1 Hz, 1
H, =CHH), 5.15–5.23 (m, 3 H, =CHH and CH2N), 6.05–6.17 (m,
1 H, =CH), 7.10–7.16 (m, 1 H, ArH), 7.31–7.39 (m, 2 H, ArH),
7.56 (dd, J1 = 2.4, J2 = 8.8 Hz, 1 H, ArH), 8.00 (s, 1 H, ArH) ppm.
13C NMR (75 MHz, [D6]DMSO): δ = 24.9, 26.2, 33.6, 47.0, 53.1,
97.7, 105.4, 105.8, 108.1, 108.4, 111.7, 112.2, 116.9, 120.5, 124.3,
133.6, 136.3, 138.6, 170.8, 174.7, 195.9 ppm. MS (ES): m/z (%) =
391.2 (100) [M + 1]+. DART-HRMS (ES+): calcd. C23H20FN2O3
391.1458; found 391.1454.
ArH), 7.40 (t, J = 7.4 Hz, 1 H, ArH), 7.54–7.60 (m, 1 H, ArH),
8.26 (d, J = 7.8 Hz, 1 H, ArH), 8.91 (s, 1 H, ArH) ppm. 13C NMR
(75 MHz, CDCl3): δ = 22.1, 25.8, 38.1, 48.3, 52.6, 67.5, 111.1,
117.5, 121.5, 121.7, 121.8, 125.6, 127.6, 129.0, 129.4, 130.5, 135.3,
135.6, 136.9, 140.7, 142.4, 143.1, 148.3, 166.3 ppm. MS (ES): m/z
(%) = 441.2 (100) [M + 1]+, 464.2 (60) [M + 23]+. C27H24N2O4
(440.1736): calcd. C 73.62, H 5.49, N 6.36; found C 73.59, H 5.67,
N 6.57.
12-Allyl-2,3,4,12-tetrahydro-1H-benzo[2,3]indolizino[8,7-b]indol-1-
Methyl
12-Benzyl-1-oxo-2,3,4,12-tetrahydro-1H-benzo[2,3]indol- one (25): The title compound was prepared following the above-
izino[8,7-b]indole-6-carboxylate (23): The title compound was pre-
pared following the above-described general procedure. Purification
by column chromatography [EtOAc/hexane, 20:80, v/v, Rf = 0.50
(EtOAc/hexane, 40:60, v/v)] gave a yellow solid with a green tinge
described general procedure. Purification by column chromatog-
raphy [EtOAc/hexane, 15:85, v/v, Rf = 0.40 (EtOAc/hexane, 30:70,
v/v)] gave a white solid (0.241 g from 0.31 g); yield 58%; m.p. 135–
137 °C. IR (KBr): ν
= 1660 (CO) cm–1. 1H NMR (300 MHz,
˜
max
(0.277 g from 0.35 g); yield 82%; m.p. 198–200 °C. IR (KBr): ν
CDCl3): δ = 2.31–2.39 (m, 2 H, CH2), 2.66 (t, J = 5.8 Hz, 2 H,
˜
max
= 1717 (CO and CO2CH3) cm–1. H NMR (300 MHz, CDCl3): δ CH2), 3.04 (t, J = 6.2 Hz, 2 H, CH2), 4.93 (d, J = 16.5 Hz, 1 H,
1
= 2.17 (t, J = 5.8 Hz, 2 H, CH2), 2.65 (t, J = 5.8 Hz, 2 H, CH2), =CHH), 5.16–5.18 (m, 3 H, =CHH and CH2N), 6.06–6.18 (m, 1
2.86 (t, J = 5.6 Hz, 2 H, CH2), 4.05 (s, 3 H, CO2CH3), 5.82 (s, 2
3690
H, =CH), 7.06 (s, 1 H, ArH), 7.26–7.30 (m, 2 H, ArH), 7.34–7.44
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 3684–3691

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(m, 2 H, ArH), 7.51 (d, J = 7.2 Hz, 1 H, ArH), 7.91 (d, J = 7.7 Hz,
1 H, ArH) ppm. 13C NMR (75 MHz, CDCl3): δ = 21.7, 23.6, 38.5,
46.8, 93.6, 107.2, 109.6, 109.8, 115.7, 116.9, 119.0, 120.5, 122.6,
123.4, 123.9, 124.4, 130.8, 132.6, 134.4, 138.8, 195.9 ppm. MS (ES):
m/z (%) = 315.3 (100) [M + 1]+. DART-HRMS (ES+): calcd.
C21H18N2O 315.1485; found 315.1497.
Supporting Information (see also the footnote on the first page of
this article): Experimental details, spectroscopic data for remaining
compounds and copies of 1H and 13C NMR spectra for all new
compounds are provided.
Acknowledgments
Two of the authors (V. S. and S. H.) gratefully acknowledge finan-
cial support from the Council of Scientific and Industrial Research,
New Delhi. The authors also acknowledge SAIF, CDRI for re-
cording of the spectroscopic and analytical data of all compounds.
This work was sponsored by the Department of Science and Tech-
nology, New Delhi under a grant (SR/SI/OC-01/2010).
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Received: March 9, 2010
Published Online: May 19, 2010
Eur. J. Org. Chem. 2010, 3684–3691
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
3691