TBAI/TBHP-catalyzed [3 + 2]cycloaddition/oxidation/aromatization cascade and online ESI-MS mechanistic studies: Synthesis of pyrrolo[2,1-a]isoquinolines and indolizino[8,7-b]indoles

Article abstract of DOI:10.1039/c5ra24629f

A facile [3 + 2]cycloaddition/oxidation/aromatization cascade reaction for the synthesis of pyrrolo[2,1-a]isoquinolines and indolizino[8,7-b]indoles has been developed. This tandem approach was accomplished by employing tert-butyl hydroperoxide (TBHP) as

Full text of DOI:10.1039/c5ra24629f

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TBAI/TBHP-Catalyzed [3+2]cycloaddition/oxidation/aromatization
cascade and online ESI-MS mechanistic studies: Synthesis of
pyrrolo[2,1-a]isoquinolines and indolizino[8,7-b]indoles
Received 00th January 20xx,
Accepted 00th January 20xx
a
a
a
a, b
DOI: 10.1039/x0xx00000x
Shalini Nekkanti, Niggula Praveen Kumar, Pankaj Sharma, Ahmed Kamal, Fabiane M.
c
d
*c, d
*a
Nachtigall, Oscar Forero-Doria, Leonardo S. Santos and Nagula Shankaraiah
www.rsc.org/
A facile [3+2] cycloaddition/oxidation/aromatization cascade reaction for the synthesis of pyrrolo[2,1-a]isoquinolines and
indolizino[8,7-b]indoles has been developed. This tandem approach was accomplished by employing tert-butyl
hydroperoxide (TBHP) as the environmental benign stoichiometric oxidant, with the catalysis of non-toxic
tetrabutylammonium iodide (TBAI) and isopropanol as the green solvent. Gratifyingly, this protocol is highly versatile, as
the construction of polycyclics could be tailored by readily available dipolarophiles. Only catalytic amount of TBAI was
required, as the hypervalent electrophilic iodine species (IOH) can be recovered in situ by oxidation with TBHP.
Furthermore, for the first time, the mechanistic aspects and the putative intermediates associated with this cascade have
been intercepted and characterized by online monitoring of the reaction by using ESI-MS/MS.
In continuation of our earlier efforts in the field of biologically
6
relevant β-carbolines and their novel approaches, we report
Introduction
the first application of the green TBAI/TBHP catalysis in the
The pyrrole ring is a common motif in numerous bioactive
alkaloids and pharmaceuticals. The pyrrolo[2,1-a]isoquinoline
core in the marine lamellarin alkaloids is responsible for their
wide spectrum of biological activities. For instance, lamellarin
[
3+2] cycloaddition/oxidation/aromatization cascade reaction
for the synthesis of pyrrolo[2,1-a]isoquinolines and
indolizino[8,7-b]indoles. Furthermore, for the first time, the
reaction mechanism and the intermediates associated with
D (
A
), is a potent inhibitor of human topoisomerase I and
) is an inhibitor of HIV integrase
Figure 1). The indolizino[8,7-b]indole core present in β-
carboline alkaloids such as harmicine ( ) and fascaplysin (D,
Figure ) has significant biological and pharmaceutical
relevance. Despite some elegant syntheses of pyrrolo[2,1-
[
3+2] cycloaddition/oxidation/aromatization cascade have
lamellarin α 20-sulfate (
B
1
been intercepted and characterized, by online monitoring of
the reaction by employing ESI-MS/MS.
(
C
1
2
3
4
a]isoquinolines and indolizino[8,7-b]indoles through [3+2]
cycloadditions, the (hypo)iodite catalyzed green protocol has
not yet been explored.
In recent times, the tetrabutylammonium iodide
(TBAI)/tert-butyl hydroperoxide (TBHP) catalytic system has
received unique attention due to its high efficiency, simple
5
operation, nontoxicity, inexpensiveness, and eco-friendliness.
a.
Department of Medicinal Chemistry,
National Institute of Pharmaceutical Education and Research (NIPER),
Hyderabad 500 037, India
Medicinal Chemistry & Pharmacology, CSIR-Indian Institute of Chemical
b.
Technology, Hyderabad 500 007, India
Fraunhofer Chile Research Foundation-Center System Biotechnology, FCR-
CSB, Nanobiotechnology Division at University of Talca, P.O. Box 747, Talca,
Chile
Laboratory of Asymmetric Synthesis, Chemistry Institute of Natural Resources,
Figure 1. Representaitive natural lamellarin (A, B) and indolizino[8,7-b]indole (C, D)
c.
alkaloids.
d.
University of Talca, P.O. Box 747, Talca, Chile
Corresponding authors E-mail: shankar.niperhyd@gov.in; lssantos@utalca.cl
1 13
Results and Discussion
*
Electronic Supplementary Information (ESI) available: H and C NMR. See
DOI: 10.1039/x0xx00000x
The initial investigations were focused on the feasibility of the
reaction between ethyl 2-(3,4-dihydroisoquinolin-2(1H)-
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yl)acetate (1a) and N-phenylmaleimide (2a). Optimization of transformation to give 3a in only 77% yield (entry 14, Table 1).
the reaction conditions towards 1,3-dipoles and electron- Finally, the best yield of 3a (95%) was obtained from the
deficient dipolarophiles were illustrated in Table 1. To our reaction of 1a (1.5 mmol), 2a (1 mmol), TBAI (10 mol%), and
o
delight, the proposed reaction between 1a and 2a does indeed 70% aqueous TBHP (3 equiv.) in isopropanol (5 mL) at 80 C for
occur in the presence of TBAI (10 mol%) and 70% aqueous 6 h (entry 5, Table 1).
TBHP (3 equiv.) in DMF to afford the product 3a in 86% yield
(entry 1, Table 1). Encouraged by this result, we then
a
Table 2. [3+2] Cycloaddition/oxidation/aromatization cascade reaction from 1 and 2
attempted to determine the ideal solvent for this
transformation. The desired product 3a was obtained in all the
tested solvents (entries 1–6), the highest yield of 95% was
observed in both acetonitrile and isopropanol (entry 2, and 5,
Table 1), and then we have chosen to proceed with
isopropanol as it is a green solvent. The reaction did not
proceed efficiently at room temperature (entry 7, Table 1) and
TBAI (10 mol%)
0% TBHP (3 equiv.)
7
2
CO R
+
EWG
2
N
N
2
CO R
isopropanol
80 oC, 6 h
1
3
EWG
R = Me, Et, t-butyl 1,4-naphthoquinone
N-substituted maleimides
N
o
N
CO Et
N
2
a minimum temperature of 80 C was found to be crucial.
CO
2
Et
N
2
CO Me
CO Et
2
O
O
N
O
O
O
O
O
N
O
N
a
Table 1. Optimization of the reaction conditions
F
a 95%, 83%b
3b 95%, 81%
b
3c 96%, 85%b
3
3d 92%
N
N
CO
2
Me
CO
2
Me
N
N
CO
2
Me
2
CO t-Bu
O
O
O
O
O
N
O
N
O
O
N
b
Entry
Catalyst
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAI
TBAB
Oxidant
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
TBHP
Oxone
Solvent
DMF
Yield (%)
F
OMe
1
2
3
4
5
6
86
3e 93%
3f 83%
3g 94%
3h 73%
CH
3
CN
95
N
toluene
42
CO
2
t-Bu
N
CO t-Bu
2
1,4-dioxane
isopropanol
1-butanol
59
O
O
O
O
N
95
81
c
d
7
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
isopropanol
nd
3j 77%
e
F
8
96
96
72
69
83
65
77
3i 78%
f
9
a
Reaction conditions: 1 (1.5 mmol), 2 (1 mmol), TBHP 70 wt % in water (3 equiv.),
g
o
b
1
0
2 2
TBAI (10 mol%), isopropanol (5 mL), 80 C, 6 h. 35% aqueous H O (3 equiv.) was
1
1
used as oxidant.
h
1
2
2 2
H O
1
3
mCPBA
TBHP
With the optimal reaction conditions established, we then
explored the substrate scope of this cascade reaction to
construct pyrrolo[2,1-a]isoquinolines. As highlighted in Table
1
4
a
Reaction conditions: 1a (1.5 mmol), 2a (1 mmol), catalyst (10 mol%), oxidant
o
b
c
d
(
3 equiv.), solvent (5.0 mL), 80 C, 6 h. Isolated yield. At room temperature.
2
,
1,4-naphthoquinone and
a
variety of N-substituted
to give the
e
f
n.d. = not detected. The amount of TBAI was increased to 20 mol%. The
maleimides (2a ) can react efficiently with 1a–c
–d
g
amount of 70% aqueous TBHP was increased to 5 equiv. The amount of TBAI
corresponding products in good to excellent yields upon
isolation. Encouraged by these results, we further examined
the scope of structural variation in tetrahydroisoquinoline
esters (methyl and tert-butyl) and allowed them to react with
the dipolarophiles, without loss in the reaction efficiency. As
shown, the reaction proceeded smoothly with all N-
substituted maleimides regardless of bearing electron-neutral
[
h]
2 2
was decreased to 5 mol%. 35% aqueous H O was used.
The yield of 3a was not increased much when the amount
of TBAI was increased up to 20 mol% (entry 8, Table 1) or
when the amount of 70% aqueous TBHP was increased to 5
equiv. (entry 9, Table 1). However, when the amount of TBAI
was decreased to 5 mol%, 3a was obtained in 72% yield (entry
(
phenyl), donating (p-methoxy phenyl) or with-drawing groups
p-fluoro phenyl). Among the tetrahydroisoquinoline esters,
(
the reactivity was found to be in the order ethyl>methyl>tert-
butyl. On the other hand, among the dipolarophiles, 1,4-
naphthoquinone gave the best yields of pyrrolo[2,1-
1
0, Table 1). This supports the catalytic efficiency of the
TBAI/TBHP oxidation system even at low concentration.
2 2
Further, when other oxidants such as 35% aqueous H O ,
a]isoquinolines (3c
, 3g and 3j; 96%, 94%, and 77%). The
oxone and mCPBA were used instead of 70% aqueous TBHP,
we obtained 3a in lower yields (entries 11–13, Table 1). Under
the same reaction conditions, TBAB can also catalyze this
reactivity of the dipolarophile, N-(p-fluoro) phenyl maleimide
(
3b
,
3e and 3i; 95%, 93%, and 78%) can be attributed to the
2
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electron withdrawing effect of the p-fluoro group. However, β- latter seems to have aromatized to the former compound.
nitrostyrenes and acrylates were also used as dipolarophiles
but did not react under the optimized reaction conditions.
H
2
O
2
is also employed as oxidant for the preparation of some
of the representative examples such as pyrrolo[2,1-
a]isoquinolines 3a 3b 3c Table 2) and indolizino[8,7-
Table 3) as it is greener oxidant compared
,
,
(
b]indoles 5a and 5b
(
a
Table 3. [3+2] Cycloaddition/oxidation/aromatization cascade reaction from 4 and 2
with TBHP.
Several mechanistic considerations and kinetic studies led
the general acceptance of the [3+2]
cycloaddition/oxidation/aromatization sequence proposed in
to
7
Scheme
intermediates are involved in the reaction of tertiary amines
) with dipolarophiles ( ) catalyzed by TBAI-TBHP. However,
these neutral zwitterionic species ( ) are expected to be in
1.
Several neutral zwitterionic and iminium
(
A
E
C
equilibrium with their protonated forms in protic solution. ESI-
MS/MS seems to be the ideal technique to investigate the
[
3+2] cycloaddition reaction mechanism and catalytic cycle,
since ESI could capture such ionic intermediates directly from
solution to the gas phase for their unprecedented MS
interception, mass identification, and MS/MS structural
8
characterization. According to our interest in organic reaction
9
mechanistic analysis by mass spectrometry (MS), which has
a
Reaction conditions: 4 (1.5 mmol), 2 (1 mmol), TBHP 70 wt% in water (3 equiv.), greatly benefited from the development of electrospray
o
b
TBAI (10 mol%), isopropanol (5 mL), 80 C, 6 h. 35% aqueous H
used as oxidant.
2
O
2
(3 equiv.) was ionization (ESI), herein, we describe the experiments aimed to
intercept the cationic species resulting from the online
monitoring of the reaction by using reactors coupled to ESI-MS
a
Table 4. [3+2] Cycloaddition/oxidation/aromatization cascade reaction from 6 and 2
in the positive-ion mode.
+
I
–
a
Reaction conditions: 4 (1.5 mmol), 2 (1 mmol), TBHP 70 wt% in water (3 equiv.),
o
b
c
TBAI (10 mol%), isopropanol (5 mL), 80 C, 6 h. No reaction. detected by GC-
d
MS. Isolated yield.
With the successful reactivity of the tandem reaction on
isoquinoline scaffolds, we then explored this method on
tetrahydro-β-carbolines to give indolizino[8,7-b]indoles and
the result was listed in Table 3. Interestingly, the target
indolizino[8,7-b]indoles (5a–f) were obtained in moderate to
good yields and the order of reactivities are similar to those
observed in the case of pyrrolo[2,1-a]isoquinolines.
Encouraged by these results, we applied our synthetic protocol
to nitrogen heterocycles such as piperidine, indoline,
pyrrolidine, and quinoline acetates (6a–d, Table 4). The
Scheme 1. Proposed mechanism.
reaction with 1,4-naphthoquinone was not successful in the
formation of 7a and 7b except for 7c, albeit in only 5% yield.
Interestingly, in the reaction with ethyl 2-(3,4-dihydroquinolin-
Initially, following our reaction protocol, the dipolarophile
(1.0 mmol) was added to mixture of
1
(2H)-yl)acetate (6d), the product obtained was pyrrolo[1,2-
a]quinoline (7d) instead of dihydropyrrolo[1,2-a]quinoline, in
8% yield. Under the TBAI/TBHP oxidative conditions, the
2
a
a
a
tetrahydroisoquinoline acetate 1a (1.5 mmol), TBAI (10 mol%),
8
and 70% aqueous TBHP (3.0 equiv.) in isopropanol (25.0 mL)
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under an air atmosphere. Then, the solution was online All solvents were purified and dried using standard methods
monitored through pressurized sample infusion (PSI) prior to use. Commercially available reagents were used
1
methodology, which allows us to screen the reaction without further purification. H NMR spectra were recorded on
0
1
o
solutions in real-time for 6 h at 80 C under stirring. Initially, an NMR instrument operated at 500 MHz. Chemical shifts are
after 20 s to 2 h of reaction, three cationic species directly reported in ppm with the solvent resonance as the internal
1
3
3
related to the proposed catalytic cycle can be observed standard (CDCl : δ 7.26 ppm). C NMR spectra were recorded
(
Scheme 1), which are detected as major ions (Figure 2a): on an NMR instrument operated at 125 MHz with complete
+
+
1a+H] of m/z 220, the main iminium intermediate [
[
B
] of m/z proton decoupling. Chemical shifts are reported in ppm with
: δ 77.16
+
N] of m/z 242. Furthermore, the proton-bond the solvent resonance as the internal standard (CDCl
2
18, and [Bu
4
3
+
dimer of 1a is also observed as [1a + H + 1a] (m/z 439). ppm). The following abbreviations were used for 1H NMR
Following the reaction by ESI-MS in the negative ion-mode spectra to indicate the signal multiplicity: s (singlet), d
gives a clean spectrum of iodide ion of m/z 127. No other (doublet), t (triplet), q (quartet) and m (multiplet). MS and
anionic species are observed in the ESI(-)-MS spectra. After 2 h HRMS were measured in EI or ESI mode and the mass analyzer
of reaction, a proton-bond dimer of m/z 437 is observed of the HRMS was TOF. Thin layer chromatography was
(
Figure 2b), which was a key transient intermediate for the performed on pre-coated glass back plates and visualized with
formation of zwitterionic species in solution. The UV light at 254 nm.
characterization of this species was performed by ESI-MS/MS Online monitoring experiments were carried out by
experiments, which afforded as expected, two main fragment overpressure in a Schlenk flask held at 2.0 psi (air) throughout
pathways producing intermediate of m/z 220, and iminium the reaction and the temperature was controlled by an oil bath
C
D
+
+
ion [
91 (Figure 2b) can be also observed in Figure 2a. The mixture was transferred to ESI ion-source directly through
B] of m/z 218. Moreover, the intermediate [F + H] of m/z through and magnetic stirrer placed in the flask. The reaction
3
+
F + H] of m/z 391 by CID PEEK tubing (200 mm in length, i.d. 0.055 mm).Mass spectra
fragmentation of the ion [
+
experiments afforded the ion [
F
+ H – CO] of m/z 363, and [
O] of m/z 317. Furthermore, the aromatization (ESI-MS) and tandem Mass (ESI-MS/MS),and the online
process can also be observed online as depicted in Figure 2b mechanistic studies were carried out by using ESI(+)-MS(/MS)
as the ion of m/z 389 starts to be produced and giving the final in a Bruker Daltonics AmaZon SLion trap equipment.
F
+
were recorded by Electrospray Ionization Mass Spectrometry
+
H – 2xCO – H
2
,
+
product of m/z 387 [3a + H] that is the protonated form of 3a
.
Typical reaction procedure. The dipolarophiles 2a
mmol) were added to a mixture of a tetrahydroisoquinoline
acetates 1a or tetrahydro-β-carboline acetates 4a (1.5
–d (1.0
–
c
–c
mmol), TBAI (10 mol%), 70% aqueous TBHP (3 equiv.), and
TBHP in isopropanol (5.0 mL) under an air atmosphere. The
o
solution was stirred for 6 h at 80 C. The crude mixture was
filtered and the precipitate washed with ethyl acetate
followed by recrystallization from chloroform to obtain the
desired products 3a–j and 5a–f.
Ethyl
9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-
pyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate
o
1
(
3a). White solid (366 mg, 95%); m.p. 190–191 C; H NMR
500 MHz, CDCl ): δ=8.59 (d, J=7.3 Hz, 1H), 7.48 (t, J=7.7 Hz,
H), 7.41–7.37 (m, 5H), 7.29 (d, J=7.1 Hz, 1H), 4.78 (t, J=6.8 Hz,
H), 4.45–4.42 (m, 2H), 3.18 (t, J=6.7 Hz, 2H), 1.46 (t, J=7.0 Hz,
(
3
2
2
3
1
1
1
3
3
H); C NMR (125 MHz, CDCl ): δ=163.0, 161.5, 159.6, 133.4,
32.5, 132.3, 130.3, 128.9, 127.9, 127.9, 127.7, 127.6, 127.1,
25.5, 125.2, 118.6, 116.2, 61.6, 43.3, 28.3, 14.7; HRMS (ESI-
+
[M+H] 387.1344, found
TOF) m/z calculated for C23
H
18
N
2
O
4
3
87.1350.
Ethyl
9,11-dioxo-10-(4-fluorophenyl)-6,9,10,11-tetrahydro-
pyrrolo[2,1-a] isoquinoline-8-
Figure 2. (a) Online ESI-MS screening of the reaction of the dipolarophile 2a (1.0 mmol),
tetrahydroisoquinoline acetate 1a (1.5 mmol), TBAI (10 mol%), 70% aqueous TBHP (3.0 5H-pyrrolo[3',4':3,4]
o
equiv.), and TBHP in isopropanol (25.0 mL) under an air atmosphere after 1:50 min. (b) carboxylate (3b). White solid (383 mg, 95%); m.p. 247–248 C;
1
Online ESI-MS spectra of the reaction after 2 h of experiments.
H NMR (500 MHz, CDCl
m, 4H), 7.30 (d, J=7.0 Hz, 1H), 7.17 (t, J=8.3 Hz, 2H), 4.77 (t,
J=6.8 Hz, 2H), 4.45–4.41 (m, 2H), 3.18 (t, J=6.8 Hz, 2H), 1.46 (t,
3
): δ=8.56 (d, J=7.0 Hz, 1H), 7.43–7.36
(
1
3
Experimental Section
J=7.17 Hz, 3H); C NMR (125 MHz, CDCl
3
): δ=163.0, 161.5,
1
59.5, 133.5, 132.4, 130.4, 128.9, 128.8, 128.0, 127.9, 127.6,
General information.
4
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1
25.4, 125.0, 118.7, 115.9, 61.6, 43.4, 28.3, 14.1; HRMS (ESI- (t, J=6.5 Hz, 2H), 4.07 (s, 3H), 3.11 (t, J=6.5 Hz, 2H); C NMR
3
1
+
TOF) m/z calculated for C23
05.1252.
H
17FN
2
O
4
[M+H] 405.1250, found (125 MHz,CDCl
133.6, 133.3, 133.0, 130.1, 128.8, 127.4, 127.4, 127.2, 126.6,
26.3, 125.4, 123.4, 117.5, 53.1, 43.2, 29.1; HRMS (ESI-TOF)
3
): δ= 179.6, 179.6, 161.8, 135.8, 135.6, 134.6,
4
1
+
Ethyl 9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo[1,2- m/z calculated for
a]isoquinoline-8-carboxylate (3c). Yellow solid (356 mg, 96%); 358.1076
C
22
H15NO
4
[M+H] 358.1079,found
.
o
m.p. 144–145 C; H NMR (500 MHz, CDCl
1
3
): δ=9.01 (d, J=7.9 tert-Butyl
9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H-
Hz, 1H), 8.31 (d, J=7.3 Hz, 1H), 8.22 (d, J=7.3 Hz, 1H), 7.74–7.68 pyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate
o
1
(
m, 2H), 7.46 (t, J=7.6 Hz, 1H), 7.38 (t, J=7.3 Hz, 1H), 7.28 (d, (3h). Orange solid (302 mg, 73%); m.p. 234–235 C; H NMR
J=7.4 Hz, 1H), 4.57–4.54 (m, 2H), 4.30 (t, J=6.5 Hz, 2H), 3.11 (t, (500 MHz, CDCl ): δ=8.59 (d, J=7.3 Hz, 1H), 7.48 (t, J=7.9 Hz,
J=6.5 Hz, 2H), 1.50 (t, J=7.1 Hz, 3H); C NMR (125 MHz, 2H), 7.40–7.35 (m, 5H), 7.29 (d, J=7.1 Hz, 1H), 4.75 (t, J=6.8 Hz,
3
1
3
1
3
CDCl
3
): δ=179.7, 179.4, 161.4, 135.6, 135.6, 134.7, 133.6, 2H), 3.17 (t, J=6.7 Hz, 2H), 1.66 (s, 9H); C NMR (125 MHz,
33.2, 132.9, 130.0, 128.8, 127.4, 127.3, 127.2, 126.6, 126.3, CDCl ): δ=163.2, 161.5, 158.9, 133.0, 132.6, 132.3, 130.1,
26.0, 123.2, 117.4, 62.4, 43.1, 29.1, 14.0; HRMS (ESI-TOF) 128.9, 127.9, 127.9, 127.7, 127.5, 127.2, 125.6, 124.6, 120.1,
1
1
3
+
m/z calculated for
72.1238
C
23
H17NO
4
[M+H] 372.1235, found 116.0, 83.4, 43.2, 28.4, 28.2; HRMS (ESI-TOF) m/z calculated
+
3
.
22 2 4
for C25H N O [M+H] 415.1657, found 415.1660.
Methyl
9,11-dioxo-10-phenyl-6,9,10,11-tetrahydro-5H- tert-Butyl
tetrahydro-5H-pyrrolo [3',4':3,4] pyrrolo[2,1-a] isoquinoline-
3d). Orange solid (342 mg, 92%); m.p. 217–218 C; H NMR 8-carboxylate (3i). Yellow solid (336 mg, 78%); m.p. 209–210
9,11-dioxo-10-(4-fluorophenyl)-6,9,10,11-
pyrrolo[3',4':3,4]pyrrolo[2,1-a]isoquinoline-8-carboxylate
o
1
(
o
1
(500 MHz, CDCl
3
): δ=8.59 (d, J=8.2 Hz, 1H), 7.49 (t, J=7.7 Hz,
3
C; H NMR (500 MHz, CDCl ): δ=8.56 (d, J=7.1 Hz, 1H), 7.42–
2
2
H), 7.42–7.36 (m, 5H), 7.30 (d, J=6.8 Hz, 1H), 4.79 (t, J=6.7 Hz, 7.37 (m, 4H), 7.29 (d, J=7.1 Hz, 1H), 7.16 (t, J=8.5 Hz, 2H), 4.75
1
3
13
H), 3.98 (s, 3H), 3.20 (t, J=6.8 Hz, 2H); C NMR (125 MHz, (t, J=6.8 Hz, 2H), 3.17 (t, J=6.7 Hz, 2H), 1.65 (s, 9H); C NMR
): δ=162.9, 161.6, 160.0, 133.6, 132.3, 130.3, 128.8, (125 MHz, CDCl ): δ=163.1, 161.5, 158.8, 133.1, 132.4, 130.2,
28.0, 127.9, 127.7, 127.6, 127.0, 125.4, 125.3, 118.1, 116.2, 129.0, 128.9, 128.5, 128.5, 127.9, 127.8, 125.5, 124.4, 120.3,
2.3, 43.4, 28.3; HRMS (ESI-TOF) m/z calculated for C22 115.9, 115.7, 83.4, 43.2, 28.3, 28.2; HRMS (ESI-TOF) m/z
CDCl
3
3
1
5
16 2 4
H N O
+
+
[M+H] 373.1188, found 373.1187.
2 4
calculated for C25H21FN O [M+H] 433.1558, found 433.1563.
Methyl 9,11-dioxo-10-(4-fluorophenyl)-6,9,10,11-tetrahydro- tert-Butyl 9,14-dioxo-5,6,9,14-tetrahydrobenzo[5,6]isoindolo
H-pyrrolo [3',4':3,4] pyrrolo[2,1-a] isoquinoline-8- [1,2-a]isoquinoline-8-carboxylate(3j). Orange solid (234 mg,
carboxylate (3e). Orange solid (362 mg, 93%); m.p. 226–227 76%); m.p. 170–171 C; H NMR (500 MHz, CDCl
5
o
1
3
): δ=9.02 (d,
): δ=8.56 (d, J=7.4 Hz, 1H), 7.43– J=7.7 Hz, 1H), 8.31 (d, J=6.8 Hz, 1H), 8.23 (d, J=6.1 Hz, 1H),
.38 (m, 4H), 7.30 (d, J=6.8 Hz, 1H), 7.16 (t, J=9.1 Hz, 2H), 4.78 7.73–7.70 (m, 2H), 7.45 (t, J=7.4 Hz, 1H), 7.38 (t, J=7.1 Hz, 1H),
o
1
C; H NMR (500 MHz, CDCl
3
7
1
3
(
t, J=6.7 Hz, 2H), 3.99 (s, 3H), 3.19 (t, J=6.8 Hz, 2H); C NMR 7.28 (d, J=7.4 Hz, 1H), 4.27 (t, J=6.4 Hz, 2H), 3.11 (t, J=6.4 Hz,
1
): δ=162.9, 161.5, 159.9, 133.7, 132.4, 130.4, 2H), 1.68 (s, 9H); C NMR (125 MHz, CDCl
3
(
125 MHz, CDCl
3
3
): δ=179.8, 179.3,
1
1
C
28.8, 128.7, 128.0, 127.9, 127.6, 125.4, 125.1, 118.2, 115.8, 160.5, 135.7, 135.0, 134.8, 133.5, 133.1, 132.8, 129.9, 128.7,
15.7, 52.3, 43.4, 28.3; HRMS (ESI-TOF) m/z calculated for 127.7, 127.4, 127.2, 126.5, 122.4, 117.1, 84.1, 43.0, 29.1, 28.0;
+
+
[M+H] 391.1094, found 391.1089.
22
H15FN
2
O
4
HRMS (ESI-TOF) m/z calculated for
00.1548, found 400.1546
C
25
H21NO
4
[M+H]
4
.
Methyl
9,11-dioxo-10-(4-methoxyphenyl)-6,9,10,11-
tetrahydro-5H-pyrrolo [3',4':3,4] pyrrolo[2,1-a] isoquinoline- Methyl
9,14-dioxo-5,9,14,15-tetrahydro-6H-
8
-carboxylate (3f). White solid (333 mg, 83%); m.p. 192–193 naphtho[2',3':1,2]indolizino[8,7-b]indole-8-carboxylate (5a).
o
1
o
1
C; H NMR (500 MHz, CDCl
.37 (m, 2H), 7.29 (t, J=8.8 Hz, 3H), 7.0 (d, J=8.8 Hz, 2H), 4.77 MHz, CDCl
t, J=7.0 Hz, 2H), 3.98 (s, 3H), 3.84 (s, 3H), 3.18 (t, J=6.8 Hz, J=7.0 Hz, 1H), 7.73–7.68 (m, 2H), 7.57 (d, J=7.9 Hz, 1H), 7.52 (d,
3
): δ=8.58 (d, J=7.3 Hz, 1H), 7.42– Red solid, yield (348 mg, 88%); m.p. 180–181 C; H NMR (500
7
3
): δ =11.25 (s, 1H), 8.27 (d, J=7.1 Hz, 1H), 8.20 (d,
(
1
3
2H); C NMR (125 MHz, CDCl
133.5, 132.3, 130.3, 128.3, 128.0, 127.9, 127.6, 125.5, 125.4, (t, J=7.4 Hz, 2H), 4.08 (s, 3H), 3.29 (t, J=7.3 Hz, 2H); C NMR
125.2, 118.0, 116.3, 114.2, 55.4, 52.2, 43.4, 28.3; HRMS (ESI- (125 MHz, CDCl ): δ=180.4, 178.6, 161.4, 136.5, 135.5, 134.5,
3
): δ=163.2, 161.9, 160.1, 158.9, J=8.0 Hz, 1H), 7.30 (t, J=7.4 Hz, 1H), 7.16 (t, J=7.3 Hz, 1H), 4.53
1
3
3
+
TOF) m/z calculated for C23
03.1301.
H
18
N
2
O
5
[M+H] 403.1294, found 133.4, 133.1, 131.9, 127.2, 126.6, 126.4, 125.5, 124.8, 124.3,
4
122.4, 120.4, 119.0, 115.5, 112.4, 110.9, 53.0, 44.6, 20.4;
+
HRMS (ESI-TOF) m/z calculated for
9,14-dioxo-5,6,9,14- 397.1188, found: 397.1185.
C
24
H
16
N
2
O
4
[M+H]
Methyl
tetrahydrobenzo[5,6]isoindolo[1,2-a]isoquinoline-8-
carboxylate (3g). Orange solid (335 mg, 94%); m.p. 205–206 Ethyl
o
9,14-dioxo-5,9,14,15-tetrahydro-6H-
1
C; H NMR (500 MHz, CDCl
3
): δ=9.0 (d, J=7.7 Hz, 1H), 8.31 (d, naphtho[2',3':1,2]indolizino [8,7-b]indole-8-carboxylate (5b).
o
J=8.6 Hz, 1H), 8.22 (d, J=8.6 Hz, 1H), 7.73–7.70 (m, 2H), 7.46 (t, Red solid (377 mg, 92%); m.p. 208–209 C; H NMR (500 MHz,
1
J=7.6 Hz, 1H), 7.39 (t, J=7.3 Hz, 1H), 7.29 (d, J=7.4 Hz, 1H), 4.30 CDCl
3
): δ=11.28 (s, 1H), 8.29–8.28 (m, 1H), 8.24–8.22 (m, 1H),
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
+
[M+H] 439.1657,
7
7
3
.74–7.69 (m, 2H), 7.58 (d, J=7.9 Hz, 1H), 7.52 (d, J=8.2 Hz, 1H), (ESI-TOF) m/z calculated for C27
H
22
N
2
O
4
.30 (t, J=8.0 Hz, 1H), 7.16 (t, J=7.9 Hz, 1H), 4.58–4.52 (m, 4H), found 439.1653
.
1
3
.30 (t, J=7.6 Hz, 2H), 1.52 (t, J=7.1 Hz, 3H); C NMR (125 MHz,
): δ=180.4, 178.4, 161.0, 136.5, 135.5, 134.5, 133.3, Ethyl
33.0, 131.7, 127.1, 127.0, 126.6, 125.5, 124.8, 124.3, 122.1, a]quinoline-13-carboxylate (7d). Yellow solid (324 mg, 88%);
CDCl
3
7,12-dioxo-7,12-dihydrobenzo[5,6]isoindolo[2,1-
1
1
o
1
20.3, 118.9, 115.4, 112.3, 110.7, 62.4, 44.5, 20.3, 14.0; HRMS m.p. 179–180 C; H NMR (500 MHz, CDCl
3
): δ=8.42 (d, J=9.3
+
[M+H] 411.1344, Hz, 1H), 8.30 (d, J=7.6 Hz, 1H), 8.26–8.19 (m, 1H), 7.94 (d, J=8.5
(ESI-TOF) m/z calculated for C25
H
18
N
2
O
4
found: 411.1334
.
Hz, 1H), 7.83 (d, J=7.7 Hz, 1H), 7.78–7.69 (m, 2H), 7.62 (t, J=7.6
Hz, 2H), 7.54 (t, J=7.7 Hz, 1H), 4.75–4.70 (m, 2H), 1.55 (t, J=7.1
1
3
Ethyl
3
2-phenyl-1,3-dioxo-1,2,3,6,7,12-hexahydropyrrolo Hz, 3H); C NMR (125 MHz, CDCl ): δ=180.5, 179.5, 163.8,
[
3',4':1,2] indolizino[8,7-b]indole-4-Carboxylate (5c). Orange 135.9, 134.8, 134.0, 133.7, 132.9, 132.6, 129.6, 129.6, 128.4,
1
o
solid (293 mg, 69%); m.p. 269–270 C; H NMR (500 MHz, 126.9, 126.7, 126.4, 125.8, 123.6, 121.3, 118.6, 116.6, 111.9,
CDCl + DMSO-d ): δ=9.37 (s, 1H), 7.51 (d, J=7.9 Hz, 1H),7.40 (t, 63.3, 13.9; HRMS (ESI-TOF) m/z calculated for C23
3
6
H25NO
4
+
J=8.0 Hz, 3H), 7.32–7.29 (m, 3H), 7.19 (t, J=7.3 Hz, 1H), 7.08 (t, [M+H] 370.1079, found 370.1083
J=7.6 Hz, 1H), 4.79 (t, J=7.4 Hz, 2H), 4.36–4.32 (m, 2H), 3.24 (t,
.
1
3
J=7.3 Hz, 2H), 1.37 (t, J=7.0 Hz, 3H); C NMR (125 MHz,
CDCl +DMSO-d ): δ=162.5, 160.7, 158.6, 137.1, 131.9, 128.1,
27.0, 126.5, 126.2, 124.8, 123.7, 123.5, 123.3, 119.9, 119.3,
18.6, 113.1, 111.6, 110.6, 60.8, 44.1, 20.1, 13.5; HRMS (ESI-
Conclusions
3
6
1
1
In summary, we have developed an environmental friendly
tandem [3+2] cycloaddition/oxidation/aromatization sequence
of tetrahydroisoquinoline and tetrahydro-β-carboline acetates
in a green solvent. This novel protocol provides a rapid and
efficient access to biologically important pyrrolo[2,1-
a]isoquinolines and indolizino[8,7-b]indoles in a highly concise
fashion. Furthermore, for the first time, key intermediates
related to proposed mechanism of this tandem reaction were
identified and characterized by online monitoring of reactions
through ESI-MS(/MS) experiments. With TBHP as the “green”
oxidant, cheap, low toxic TBAI as the catalyst, and isopropanol
as the green solvent, this protocol would be more attractive in
the field of green chemistry.
+
TOF) m/z calculated for C25
26.1450
19 3 4
H N O [M+H] 426.1453, found:
4
.
Ethyl
2-(4-methoxy)phenyl-1,3-dioxo-1,2,3,6,7,12-
hexahydropyrrolo[3',4':1,2]indolizino[8,7-b]indole-4-
Carboxylate (5d). Yellow solid (304 mg, 67%); m.p. 202–203
o
1
C; H NMR (500 MHz, CDCl
3
): δ=9.06 (s, 1H), 7.60 (d, J=7.7 Hz,
1
1
2
H), 7.44 (d, J=8.0 Hz, 1H), 7.32–7.28 (m, 3H), 7.18 (t, J=7.4 Hz,
H), 7.01 (d, J=8.6 Hz, 2H), 4.88 (t, J=7.3 Hz, 2H), 4.45–4.41 (m,
H), 3.85 (s, 3H), 3.32 (t, J=7.9 Hz, 2H), 1.46 (t, J=7.1 Hz, 3H);
1
3
3
C NMR (125 MHz, CDCl ): δ=163.8, 161.9, 159.5, 159.0,
1
1
4
37.5, 128.2, 127.0, 125.5, 125.1, 124.5, 124.2, 124.0, 121.3,
20.7, 120.0, 119.3, 114.3, 113.9, 112.0, 111.1, 61.6, 55.4,
4.8, 20.9, 14.1; HRMS (ESI-TOF) m/z calculated for C26
+
H
21
N
3
O
5
Acknowledgements
[M+H] 456.1559, found 456.1564
.
SN, NPK, and PS are thankful to DoP, Ministry of Chemicals and
Fertilizers Govt. of India, New Delhi for the award of Research
Fellowship. FMN and LSS acknowledge InnovaChile CORFO
Code FCR-CSB09CEII-6991 and Anillo Cientifico FONDECYT ACT-
Ethyl
2-(4-fluoro)phenyl-1,3-dioxo-1,2,3,6,7,12-
hexahydropyrrolo[3',4':1,2]indolizino[8,7-b]indole-4-
Carboxylate (5e). Yellow solid (318 mg, 72%); m.p. 259–260 C;
o
1
107 for supporting this research activity. FMN thanks
1
3
H NMR (500 MHz, CDCl ): δ=9.04 (s, 1H), 7.60 (d, J=7.9 Hz,
FONDECYT-Iniciacion (11130086). LSS thanks additional
support from PIEI (Quimica y Bio-organica en Recursos
Naturales) Universidad de Talca.
1
3
2
H), 7.44–7.38 (m, 3H), 7.30 (t, J=7.3 Hz, 1H), 7.18 (t, J=8.3 Hz,
H), 4.88 (t, J=7.1 Hz, 2H), 4.45–4.43 (m, 2H), 3.31 (t, J=7.3 Hz,
3
H), 1.47 (t, J=7.0 Hz, 3H); C NMR (125 MHz, CDCl ):
3
1
δ=163.5, 162.7, 161.4, 159.4, 137.6, 128.7, 128.6, 125.5, 124.6,
1
24.1, 123.7, 120.8, 120.2, 119.4, 116.0, 115.8, 113.7, 112.0,
11.3, 61.7, 44.8, 20.8, 14.1; HRMS (ESI-TOF) m/z calculated Notes and references
1
+
3 4
for C25H18FN O [M+H] 444.1359, found 444.1359.
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2
naphtho[2',3':1,2]indolizino[8,7-b]indole-8-carboxylate (5f).
o
1
,
Red solid (275 mg, 63%); m.p. 199–200 C; H NMR (500 MHz,
CDCl ): δ=11.26 (s, 1H), 8.28 (d, J=8.8 Hz, 1H), 8.23 (d, J=8.8 Hz,
H), 7.73–7.69 (m, 2H), 7.56 (d, J=7.9 Hz, 1H), 7.52 (d, J=8.2 Hz,
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3
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2
,
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