Transition-metal-free catalyzed [3+2] cycloadditions/oxidative aromatization reactions for the synthesis of annulated indolizines

Article abstract of DOI:10.1039/c9nj03076j

In this study, transition-metal-free catalyzed [3+2] cycloadditions/oxidative aromatization three-component reactions for the successful direct construction of pyrrolo[3,4-a]indolizine-1,3(2H)-diones via pyridinium ylides are reported. This method utilize

Full text of DOI:10.1039/c9nj03076j

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Transition-metal-free catalyzed [3+2]
cycloadditions/oxidative aromatization reactions
for the synthesis of annulated indolizines†
Cite this: New J. Chem., 2019,
43, 17000
Qianwei Zhang, Bin Wang, Huifang Ma and Keyume Ablajan
*
In this study, transition-metal-free catalyzed [3+2] cycloadditions/oxidative aromatization three-
component reactions for the successful direct construction of pyrrolo[3,4-a]indolizine-1,3(2H)-diones
via pyridinium ylides are reported. This method utilizes readily available pyridines, acetophenones and
maleimides as starting materials in the presence of TBAI (N-tetrabutylammonium iodide)/TBHP (tert-butyl
hydroperoxide), with a wide substrate scope and moderate to good yields, avoiding the use of metal
catalysts and generation of halides.
Received 13th June 2019,
Accepted 4th October 2019
DOI: 10.1039/c9nj03076j
rsc.li/njc
Introduction
N-Fused heterocyclic compounds are one of the most important
structural in organic compounds, and they are widely used in
pharmaceutical1 and organic material chemistry.2 Indolizines
are special structural units of N-fused heterocyclic compounds in
that they have a broad array of biological3 and pharmaceutical4
functions such as antitumor,5 antimycobacterial,6 antagonist,7
and antiproliferative activities.8
The synthesis of indolizines has received extensive attention
from the field of organic synthesis methodology in recent years.
Main approaches for indolizine synthesis are the 1,3-dipolar
cycloaddition of pyridinium ylides with alkenes9 or alkynes,10
cyclization of pyridines with a free C-2 position,11 cyclization of
2-alkylpyridines with alkenes,12 alkynes13 or bromomethyl acyl-
boronates,14 cyclization of 2-pyridine derivatives,15 cyclization
of 2-halo- or 2-triflylpyridines with alkynes,16 and multicomponent
reactions.17 Among which pyridinium ylides are a class of important
intermediates for multicomponent reactions of methods to generate
indolizines (Scheme 1). Traditionally, the methods used to generate
pyridinium ylides mainly involve the reaction of pyridines with acyl
bromides17j,m or aryl ketones17f using halogenated metal catalysts
(Scheme 1a–c). It has been recently found that the formation of
pyridinium ylides mainly involves the use of metal catalysts from
pyridines and diazo compounds (Scheme 1d).17g However, these
approaches suffer from some drawbacks such as the use of
expensive or inexpensive transition metal catalysts and generation
Scheme 1 Direct construction of indolizine derivatives via an intermedi-
ate of pyridinium ylides.
of halides. Herein, in the interest of green chemistry and atom
economy, we report the direct synthesis of pyrrolo[3,4-a]indolizine-
1,3(2H)-diones from pyridines, acetophenones and maleimides
under transition-metal-free catalytic conditions (Scheme 1e).
Results and discussion
Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education & Xinjiang
Uyghur Autonomous Region, College of Chemistry and Chemical Engineering,
Xinjiang University, Urumqi 830046, P. R. China. E-mail: ablajan209@hotmail.com
† Electronic supplementary information (ESI) available: General experimental
information, and NMR spectra. See DOI: 10.1039/c9nj03076j
We commenced our studies using pyridine (1a), acetophenone (2a)
and N-phenylmaleimide (3a) as the model substrates with various
catalysts and oxidants to screen the optimal reaction conditions,
and the details are summarized in Table 1. Initially, heating the
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Table 1 Optimization of the reaction conditionsa,b
Iodine source
(mol%)
Oxidant
(equiv.)
Temp.
(1C)
Yield
(%)
Entry
Solvent
1
2
3
4
5
6
7
8
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
I2 (20)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
H2O2 (3)
O2
K2S2O8 (3)
TBHP (4)
TBHP (6)
TBHP (8)
TBHP (6)
TBHP (6)
TBHP (6)
TBHP (6)
EtOH
EtOAc
DCM
CH3CN
H2O
DMF
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
80
90
100
50
n.d.
n.d.
n.d.
23
45
54
66
30
42
Trace
Trace
45
n.d.
70
84
80
54
87
85
Trace
9
NIS (20)
KI (20)
10
11
12
13
14
15
16
17
18
19
20
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (20)
TBAI (10)
TBAI (20)
TBAI (20)
TBAI (20)
Scheme 2 Scope of methyl ketones.a,b a Reaction conditions: 1a (1 mmol),
2 (0.5 mmol), 3a (0.75 mmol), TBAI (20 mol%), and TBHP (6.0 equiv.) in
DMSO (3 mL) at 90 1C for 18 h; b isolated yields.
a
Reaction conditions: 1a (1 mmol), 2a (0.5 mmol), 3a (0.75 mmol),
catalyst (20 mol%), and TBHP (70% in water, 6.0 equiv.) in DMSO
(3 mL) at 90 1C for 18 h; after disappearance of the reactant 2a
of aryl methyl ketones have minimum impact on the efficiency
of this reaction, and these substrates were smoothly converted
into the corresponding products in moderate to good
b
(monitored by TLC). Isolated yields.
reactants in EtOH at 80 1C for 18 h in the presence of 20 mol% of yields. For example, the substrates bearing electronically neutral
TBAI and 3 equiv. of TBHP, we did not detect the formation of (4-H and 4-CH3), electron-rich (4-OCH3, 4-OH, and 4-NH2) and
product 4a (Table 1, entry 1).
electron-deficient (4-NO2) groups on aryl methyl ketones
Unfortunately, changing solvent such as EtOAc and DCM proceeded smoothly to afford the desired products in good
also did not give the desired product 4a (Table 1, entries 2 and 3). yields (4a–4f). Aryl methyl ketones bearing halogenated (4-F,
Gratifyingly, solvents such as CH3CN, H2O, DMF and DMSO were 4-Cl and 4-Br) substrates reacted well to obtain the desired
continuously changed to get the desired product 4a (Table 1, products in moderate yields (4g–4i). In addition, other substrates
entries 4–7). However, when using DMSO as a solvent, product 4a such as heterocyclic (2-furyl and 2-thienyl) or 1-naphthyl and
was isolated with the highest yield of 66% (Table 1, entry 7). 2-naphthyl methyl ketones for aryl methyl ketones were tolerated,
Further investigations of other kinds of iodine sources such as I2, and they delivered the expected products in moderate to excellent
NIS (N-iodosuccinimide) and KI were performed in the reaction yields (4j–4n).
and low yields were obtained (Table 1, entries 8–10). Using other
In order to further study the substrate universality of the
different oxidants such as H2O2, O2 and K2S2O8 were also reaction, we then investigated the scope of pyridines 1 and
examined; among them, TBHP was found to be the most efficient maleimides 3 under optimal conditions, as summarized in
oxidant (Table 1, entries 7 and 11–13). Further research found Scheme 3. Initially, other different N-substituted maleimides
that the amount of oxidants has a great impact on the yields of or 1,4-naphthalene was tested in this reaction, and we got the
4a; therefore, we increased the amount of oxidants to give the corresponding products (5a–5f). To our delight, 2-methylpyridine
desired product 4a in 84% yield under 6 equiv. of TBHP was also reactive, producing the desired product (5g), and there was
(Table 1, entries 14–16). We also investigated the amount of no obvious hindering effect in this reaction under the same
TBAI, and 10 mol% of TBAI led to a declined yield of 54% of conditions. In addition, we did the same reaction with quinoline
4a (Table 1, entry 17). Finally, we investigated the effect of or isoquinoline, and the results indicated that the corresponding
temperature, and the yield was further increased to 87% at products (5h–5l) were also obtained.
90 1C (Table 1, entries 18–20).
To test the practicality of this reaction, a gram-scale reaction
Under optimal reaction conditions in hand (Table 1, entry 18), using 10 mmol acetophenone (2a) with pyridine (1a) and N-phenyl-
we next began to investigate the substrate scope of aryl methyl maleimide (3a) was carried out in Scheme 4. The product 4a was
ketones 2a as summarized in Scheme 2. The electronic properties obtained in a yield of 68% (2.491 g).
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Scheme 5 Control experiments.
Scheme 3 Scope of pyridines and maleimides.a,b a Reaction conditions:
1 (1 mmol), 2a (0.5 mmol), 3 (0.75 mmol), TBAI (20 mol%), and TBHP
(6.0 equiv.) in DMSO (3 mL) at 90 1C for 18 h; b isolated yields.
Scheme 6 Possible mechanism.
instead of acetophenone 2a, participates in the reaction under
the same conditions, and can also smoothly obtain the target
product 4a (Scheme 5c and d). This further proves that A and B
would be key intermediates in this reaction.
Scheme 4 Gram-scale reaction.
Based on the above research and related reports, a plausible
To gain insights into the mechanism, the following control mechanism was proposed in Scheme 6. First, the starting material
experiments were performed in Scheme 5. The reaction was not acetophenone 2a was converted into a-iodoacetophenone A, which
inhibited in the presence of free-radical scavenger TEMPO reacts with pyridine 1a to form the pyridinium ylide B. Then, the
(2,2,6,6-tetramethylpiperidinooxy) (Scheme 5a). The result indicated concomitant release in the presence of a base afforded azomethine
that this reaction was not a radical process. The template reaction ylide C, and subsequently, the intermediate D was formed from
can smoothly react when 1.2 equiv. of I2 was added, which indicates azomethine ylide C and N-phenylmaleimide 3a via a 1,3-dipolar
that I2 plays an important role in the whole cycle process cycloaddition reaction. Finally, the intermediate D was oxidized to
(Scheme 5b). The pyridinium ylide B or a-iodoacetophenone A, the desired product 4a.
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Conclusions
In summary, we have developed novel and efficient TBAI/
TBHP-catalyzed [3+2] cycloadditions/oxidative aromatization
three-component reactions for the direct construction of pyrrolo-
[3,4-a]indolizine-1,3(2H)-diones via pyridinium ylides. This
method utilizes unfunctionalized pyridines, acetophenones
and maleimides as simple and readily available starting materials
under transition-metal-free conditions, avoiding the use of metal
catalysts and generation of halides. Furthermore, another strategy
for the synthesis of indolizines is going on in our laboratory.
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There are no conflicts to declare.
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Acknowledgements
This work was supported by the National Science Foundation of
China (No. 21961038, 21462041) and Natural Science Foundation
for Distinguished Young Scholars of Xinjiang Uyghur Autonomous
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