Synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones via the I2-promoted reactions of methyl ketones with pyridines and 1,4-naphthoquinone

Article abstract of DOI:10.1016/j.tetlet.2021.153235

An effective synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones has been achieved via the I₂-promoted reactions of methyl ketones, pyridines and 1,4-naphthoquinone. In this reaction, either aromatic or aliphatic methyl ketones proceeded well. The advantages of this method include a broad substrate scope, metal-free reaction conditions, and high atom- and step-economy.

Full text of DOI:10.1016/j.tetlet.2021.153235

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Synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones via the I2-promoted re‐
actions of methyl ketones with pyridines and 1,4-naphthoquinone
Yun Liu, Hui Xu, Hui Wu
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DOI:
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S0040-4039(21)00469-X
https://doi.org/10.1016/j.tetlet.2021.153235
TETL 153235
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Tetrahedron Letters
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22 March 2021
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Please cite this article as: Liu, Y., Xu, H., Wu, H., Synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones via the
I2-promoted reactions of methyl ketones with pyridines and 1,4-naphthoquinone, Tetrahedron Letters (2021), doi:
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Synthesis of Benzo[f]pyrido[1,2-a]indole-6,11-diones via the
I2-Promoted Reactions of Methyl Ketones with Pyridines and
1,4-Naphthoquinone
Yun Liu,* Hui Xu, Hui Wu*
School of Chemistry and Material Science, Jiangsu Normal University, Xuzhou 221116, Jiangsu, P.
R. China
Email: liu__yun3@sina.com
Abstract: An effective synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones has been achieved via
the I2-promoted reactions of methyl ketones, pyridines and 1,4-naphthoquinone. In this reaction,
either aromatic or aliphatic methyl ketones proceeded well. The advantages of this method include a
broad substrate scope, metal-free reaction conditions, and high atom- and step-economy.
Keywords: iodine, pyridines, methyl ketones, 2,3-annulated iodolizines, metal-free
Indolizine derivatives exhibit various pharmaceutical activities and play important roles in the
development of new pharmaceuticals for the treatment of human diseases [1-5]. Among these
compounds, annulated indolizines are found in several naturally occurring alkaloids [6] and have
interesting biological activities, as well as optical and electrochemical properties [7]. Consequently,
there has been growing interest in the synthesis of annulated indolizines [8-9].

Benzo[f]pyrido[1,2-a]indole-6,11-diones are naphthoquinone-fused indolizines. Traditional
synthetic routes to these compounds usually start from functionalized naphthoquinones (Scheme 1a
and 1b) [10-11]. Obviously, the direct synthesis of these compounds from unsubstituted
naphthoquinone is more convenient, and our group has reported
a
synthesis of
benzo[f]pyrido[1,2-a]indole-6,11-diones via the copper-catalyzed reaction of 1,4-naphthoquinone
with bromides and pyridines (Scheme 1c) [12]. Despite the usefulness of this method, it still requires
the preparation or purchase of expensive and irritant bromoketones. Therefore, it is desirable to use
more readily-available reactants to replace bromoketones in this reaction.
Molecular iodine has been widely used in organic chemistry [13-14]. As part of our continued
interest in heterocycle synthesis [15], herein, we describe an effective synthesis of
benzo[f]pyrido[1,2-a]indole-6,11-diones via the iodine-promoted reaction of methyl ketones with
pyridine and naphthoquinone under metal-free conditions (Scheme 1d). Due to eliminating the use of
bromoketones, this reaction features high atom- and step-economy.

Scheme 1. Synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones.
To optimize the reaction conditions, we chose the model reaction of pyridine 1a, acetophenone
2a and 1,4-naphthoquinone 3. Initially, by heating a mixture of 1a (1.5 mmol), 2a (0.6 mmol), 3 (0.5
o
mmol) and iodine (0.5 mmol) in DMF at 90 C for 12 h in a sealed tube, we obtained the desired
product 4a in 58% yield (Table 1, entry 1). Subsequently, we investigated the effect of different
solvents and found acetonitrile was the optimal choice (Table 1, entries 1-5). Optimization of the
iodine loading showed that 2 equiv. of iodine was necessary to ensure high reaction efficiency,
affording 4a in 78% yield (Table 1, entries 3, 6-7). Adding an external base did not improve the yield
(Table 1, entries 8-9). We also tested other iodine reagents instead of molecular iodine, but lower
yields were obtained (Table 1, entries 6, 10-11). Finally, we lowered the reaction temperature to 60
oC, but only isolated 4a in 59% yield (Table 1, entry 12). Therefore, the optimal conditions were
determined as heating a mixture of 1a (1.5 mmol), 2a (0.6 mmol) and 3 (0.5 mmol) in CH3CN at 90
oC for 12 h in the presence of 2 equiv. of iodine (Table 1, entry 6).
Table 1. Optimization of the reaction conditions.a
Entry
Solvent
Adduct (eq.)
Base (eq.)
Yield
(%)b
58
4a
1
2
3
DMF
I2 (1)
I2 (1)
I2 (1)
/
/
/
DCE
55
CH3CN
61

4
C6H6
I2 (1)
/
40
52
78
78
76
77
50
46
59
5
1,4-Dioxane I2 (1)
/
6
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
I2 (2)
/
7
I2 (2.5)
I2 (2)
/
8
K2CO3 (1)
9
I2 (2)
Cs2CO3 (1)
10
11
12c
NIS (2)
ICl (2)
I2 (2)
/
/
/
a
o
Reagents and conditions: 1a (1.5 mmol), 2a (0.6 mmol), 3 (0.5 mmol), adduct, base, 90 C, 12 h,
sealed tube. b Isolated yields. c 60 oC.
With the optimized conditions in hand, we then screened the scope of methyl ketones 2 by
reacting with 1a and 3 (Table 2). Various aromatic methyl ketones 2b-j were suitable substrates and
electronic or steric factors on the benzene ring substituent had little effect on the reaction. For
instance, para-substituted acetophenones 2b-f with either electron-donating groups (Me, Et) or
electron-withdrawing groups (F, Cl, Br) showed good reactivity and gave products 4b-f in 73-87%
yield. Similarly, acetophenones 2g-j with ortho- or meta-substituents reacted equally well, affording
products 4g-j in 65-77% yield. Additionally, aliphatic methyl ketones 2k-l gave products 4k and 4l in
good yields. Due to their low boiling points, an excess of the aliphatic methyl ketones was added to
the reaction system.
Table 2. Scope of methyl ketones 2.a,b

a
b
Reagents and conditions: 1a (1.5 mmol), 2b-l (0.6 mmol), 3 (0.5 mmol), iodine (1.0 mmol).
Isolated yields. c 1 mL of the aliphatic methyl ketone was used.
Next, we investigated the scope of the pyridines 1 by reacting with acetophenone 2a and

naphthoquinone 3 (Table 3). The reactions of 4-substituted pyridines 1b-c with different substituents
(CO2Et, Me), gave products 5a-b in good yields. For 3-substituted pyridine 1d, two isomers 5c and
5d were formed in 50% and 31% yield, respectively. Annulated pyridine 1e also proved to be a good
substrate, giving 5e in 86% yield. To further examine the generality of this protocol, isoquinoline 1e
was reacted with substituted acetophenones and naphthoquinone, affording product 5f-h in high
yields. Aliphatic methyl ketones also afforded products 5i-k in 62-75% yield. The structures of all
compounds were all confirmed by NMR spectroscopy and HPLC, and the spectral data of known
compounds 4a and 5e were in accordance with our previous reports [11,12].
Table 3. Scope of pyridines 1.a,b

a
b
Reagents and conditions: 1b-e (1.5 mmol), 2 (0.6 mmol), 3 (0.5 mmol), iodine (1.0 mmol).
c
d
Isolated yields. 2 (3.0 mmol) and iodine (2.0 mmol) in DMF was used. 1 mL of the aliphatic
methyl ketone was used.
Control experiments were carried out to shed light on the reaction mechanism. First, pyridinium
salt 6 was reacted with naphthoquinone 3 and pyridine 1a, which gave 4a in 83% yield (Scheme 2a).
Second, pyridinium salt 7 [16] was reacted with acetophenone and pyridine, which gave 4a in 80%
yield (Scheme 2b). These results indicated that 6 and 7 were possible reaction intermediates. Third,
we added 1 equiv. of TEMPO into the model reaction, and found the formation of 4a was not
suppressed. This dispelled the radical reaction mechanism (Scheme 2c).

Scheme 2. Control experiments.
According to our experimental results and previous literature [12,16,17], a possible mechanism
was proposed (Scheme 3). Initially, intermediate 6 is formed from the reaction of 2a with 1a with the
aid of iodine via an Ortoleva-King reaction [17]. Meanwhile, intermediate 7 is generated via the
reaction of 1a and 3. Then, the reaction of 6 with 7 by a cyclization-elimination-oxidation process
affords the final product 4a. In this reaction process, iodine plays a dual role by acting both as a
coupling reagent to transfer 2a to 6, and as an oxidant to form product 4a by oxidative aromatization.

Scheme 3. Possible reaction mechanism.
In conclusion, we have reported an efficient and practical protocol for the synthesis of
benzo[f]pyrido[1,2-a]indole-6,11-diones via the iodine-promoted reactions of methyl ketones,
pyridine, and naphthoquinone. In addition to the high atom- and step-economy, this method also has
the advantage of using readily-available methyl ketones instead of the often more difficult to access
bromoketones, allowing a substantial expansion of the reaction scope.
Acknowledgements
This work was supported by the Natural Science Research Project of Jiangsu Higher Education
Institutions (17KJB150016).
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Highlights
Synthesis of benzo[f]pyrido[1,2-a]indole-6,11-diones
Preparation of products in good yields
Broad substituents scope and metal-free conditions