One-Pot Synthesis of Indolizines Using TBHP as the Methylene Source Under Metal-Free Condition

Article abstract of DOI:10.1002/ejoc.201901803

An I₂/tert-butyl hydroperoxide (TBHP)-mediated [2+1+1+1] cycloadditions/oxidative aromatization reactions for the synthesis of indolizines using the one-pot cascade process have been developed. A variety of aryl methyl ketones react with pyridi

Full text of DOI:10.1002/ejoc.201901803

DOI: 10.1002/ejoc.201901803
Communication
Indolizines
One-Pot Synthesis of Indolizines Using TBHP as the Methylene
Source Under Metal-Free Condition
[a]
[a]
[a]
[a]
[a]
Qianwei Zhang, Keyume Ablajan,* Bin Wang, Huifang Ma, and Zhongqi Guo
Abstract: An I2/tert-butyl hydroperoxide (TBHP)-mediated free reaction. This method utilizes readily available starting ma-
2+1+1+1] cycloadditions/oxidative aromatization reactions for terials and TBHP acted in this reaction not only as oxidant and
[
the synthesis of indolizines using the one-pot cascade process radical initiator but also as a methylene source, therefore pro-
have been developed. A variety of aryl methyl ketones react viding a novel method of atom economy for the synthesis of
with pyridine/isoquinoline and TBHP in the transition-metal- indolizines.
Indolizines are one of the most important structural units of Chen and co-workers developed a catalyst-free annulation of 2-
the nitrogen-fused heterocyclic compounds, and they are pyridyl acetates and ynals with molecular oxygen for the access
[
12a]
widely found in the natural products and organic synthetic to 3-acylated indolizines (Scheme 1b).
Very recently, Shu
compounds. Functionalized indolizine derivatives have diverse and co-workers disclosed a similar protocol for the synthesis of
[
1]
[1a]
biological activities, such as antiproliferative, antimycobac- indolizine derivatives that were trifluoroacetic acid (TFA)-medi-
[
1b]
[1c]
[1d]
terial,
antitumor,
antagonist,
and also applied to high ated cascade oxidation/1,3-dipolar cycloaddition reaction of
[
2]
performance materials. Therefore, the preparation of indoliz- pyridinium ylides with DMSO in the presence of trimethylethyl-
[
16a]
ine derivatives has an urgent need in the fields of medicinal enediamine (TMEDA) and K
chemistry and organic synthetic chemistry.
we have also successfully developed an I
tert-Butyl peroxide play a different role in a wide range of [2+1+1+1] cycloadditions/oxidative aromatization reactions
S
O
(Scheme 1c).
Meanwhile,
2
2
8
/TBHP-mediated
2
[
3]
applications in organic synthesis, and usually used as oxidant
from pyridine/isoquinoline, acetophenones and TBHP using the
[
4]
and radical initiator. In addition, tert-butyl peroxide can partic- one-pot cascade process for the direct synthesis of indolizine
ipate in the organic reaction as reactant, and can provide a derivatives (Scheme 1d).
[
5]
[6]
[7]
structural skeleton of O, CH3, and tBuO2 etc. for the or-
ganic compounds. Recently, there have been many reports on
the use of tert-butyl peroxide as a carbon source to provide a
[
6]
“
CH ” skeleton. For example, Yang and co-workers reported a
3
copper-catalyzed methylation of sulfonyl hydrazides, in which
organic peroxide served as a methylating reagent.[ Different
synthetic strategies for indolizine derivatives have been exten-
sively completed. The main methods of which include 1,3-di-
polar or 1,5-dipolar cycloaddition of pyridinium ylides with alk-
6b]
[
8]
[9]
enes or alkynes and some other cyclization reactions, such
as cyclization of 2-triflylpyridines or 2-halopyridines and alk-
[
10]
[11]
ynes, cyclization of 2-pyridine derivatives, cyclization of 2-
[
12]
[13]
alkylpyridines and alkenes,
boronates, cyclization of pyridines with a free C-2 position,
and multicomponent reactions.
alkynes
or bromomethyl acyl-
[
14]
[15]
[
16]
Recently, Douglas and co-
workers have developed an iron-catalyzed indolizines synthesis
[
16f]
from pyridines, diazo Compounds, and alkynes (Scheme 1a).
[
a] Key Laboratory of Oil & Gas Fine Chemicals, Ministry of Education &
Xinjiang Uyghur Autonomous Region, College of Chemistry and Chemical
Engineering, Xinjiang University
Scheme 1. Direct construction of indolizine derivatives.
Urumqi 830046, PR China
E-mail: ablajan209@hotmail.com
http://ogfc.xju.edu.cn/info/1050/1328.htm
Supporting information and ORCID(s) from the author(s) for this article are
available on the WWW under https://doi.org/10.1002/ejoc.201901803.
On the basis of our previous research interest in the con-
[
16b]
struction of indolizines,
we started our investigation with
pyridine 1a, acetophenone 2a and TBHP 3a as the model sub-
strates. Initially, in the presence of I2 (1 equiv.) and TBHP
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Communication
(
6 equiv.), the reaction of 1a with 2a in DMSO at 120 °C for in 45 % and 78 % (Table 1, entries 23 and 24). Finally, other
12 h gave indolizine 4a in 35 % yield (Table 1, entry 1). When temperatures were tested, all of which resulted in lower yields
using KI and TBAI (N-tetrabutylammonium iodide) as the source (Table 1, entries 25 and 26).
of iodine, we did not detect the formation of product 4a
After getting the optimal reaction conditions (Table 1, entry
2), the substrate scopes of the various aryl methyl ketones 2
(
(
Table 1, entries 2 and 3). Next, other oxidants such as DTBP
di-tert-butyl peroxide), BPO (benzoyl peroxide) and K S O by
2
2
2
8
were investigated in Scheme 2. First, different substituted aceto-
phenones 2 on reaction with pyridine 1a and TBHP 3a gave
moderate to good yields of indolizines 4. For examples, the
substrates bearing various electron-neutral (4-H, 2-CH , 3-CH ,
replacing TBHP were examined, and the reaction did not pro-
ceed smoothly (Table 1, entries 1, 4–6). Control experiment
showed that this reaction did not produce 4a without adding
an oxidant (Table 1, entry 7). To our delight, by increasing the
amount of TBHP (Table 1, entries 8–11), the yields of indolizine
3
3
and 4-CH3), electron-donating (3-OCH3, 4-OCH3 and 4-
OCH CH ) and electron-withdrawing (4-Ph) groups on the
2
3
4
(
a were improved drastically to 74 % under 12 equiv. of TBHP
Table 1, entry 10). Solvent screening indicated that other sol-
vents such as H O, DMF, CH CN and PhCH or solvent free were
acetophenones proceeded smoothly to deliver the expected
products 4a–4h in 68 to 80 % yields. Halogen-substituted sub-
strates were compatible to obtain products 4i–4o in good
yields. Furthermore, aromatic heterocycle, such as 2-furyl and
2
3
3
not effective at all (Table 1, entries 12–16). In order to further
increase the yield, different bases and acids such as DBU
2
-thienyl, or 1-naphthyl and 2-naphthyl methyl ketone sub-
(
[
1,8-diazabicyclo[5.4.0]undec-7-ene), DABCO (1,4-diazabicyclo-
2.2.2]octane), Et N, TsOH, PhCOOH and AcOH were applied as
strates also underwent reaction and afforded the desired prod-
ucts 4p–4s in yields of 64 % to 82 %. To our delight, the desired
product 4t was obtained smoothly in 45 % yield by replacing
the pyridine 1a substrate with isoquinoline 1b. When alkyl
methyl ketone (butanone 2u), 4-(N,N-dimethylamino)pyridine
3
additives. The results showed that AcOH can increase the yield
of this reaction notably (Table 1, entries 17–22). We also investi-
gated 0.5 and 1 equiv. of I that led to declined yield of 4a
2
1c and quinoline 1d as the substrates, unfortunately, those re-
actions were not allowed to obtain the desired products 4u, 4v
and 4w.
Table 1. Optimization of the reaction conditions.[a]
In order to clarify the reaction mechanism, a series of control
experiments were performed in Scheme 3. First, the reaction
was inhibited in the presence of free-radical scavenger 2,2,6,6-
tetramethylpiperidinooxy (TEMPO) (Scheme 3a) and butylated
hydroxytoluene (BHT) (Scheme 3b). This implied that the reac-
tion was a radical process. To determine the source of methyl-
Yield[b]
[%]
ene in this reaction, we used [D ]DMSO as the reaction solvent,
and did not observe deuterium on the H-NMR spectrum
Iodine
source
Oxidant
[equiv.]
Additive
[equiv.]
Solvent
6
1
Entry
[
equiv.]
(Scheme 3c). This shows that the methylene source was not
1
2
3
4
5
6
7
8
9
I
2
(1)
TBHP (6)
TBHP (6)
TBHP (6)
DTBP(6)
BPO (6)
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
/
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
35
from DMSO. If no AcOH and DMSO were added under standard
conditions, and the target product 4a was still found in the
product (Scheme 3d). Thus, further eliminating that the methyl-
ene source was derived from AcOH and DMSO. Next, we tested
intermediate process that might go through this reaction. When
the reaction was performed from only pyridinium salt B expect-
edly 4a was not smoothly formed under standard conditions
KI (1)
TBAI (1)
n.d
n.d
trace
n.d
n.d
n.d
52
65
74
73
42
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
I
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(1)
(0.5)
(2)
(1)
(1)
K
/
2
S
2
O
8
(6)
TBHP (8)
TBHP (10)
TBHP (12)
TBHP (14)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
TBHP (12)
(Scheme 3e). However, this reaction can proceed smoothly if
10
11
12
13
14
15
16
17
18
19
20
21
pyridine was involved (Scheme 3f), indicating that pyridinium
salt B would be the key intermediate and pyridine 1a also acts
as a base in this reaction.
H
2
O
DMF
CH CN
23
18
3
According to the experimental research above and related
PhCH
/
3
trace
30
trace
trace
32
trace
trace
80
45
78
74
69
[
6]
reports, a plausible mechanism was suggested in Scheme 4.
Initially, acetophenone 2a was formed α-iodoacetophenone A,
which reacts with pyridine 1a to furnishes the pyridinium salt
B. The concomitant release of HI afforded azomethine ylide C.
Meanwhile, TBHP was activated by heating to obtain tert-but-
DBU
DABCO
Et N
3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
TsOH
PhCOOH
AcOH
AcOH
AcOH
AcOH
AcOH
[
6a]
2
2
I
2
oxy radical 5, and further decomposed into methyl radical 6
23
24
25
26
I
I
I
I
2
2
2
2
[6f,17]
and acetone 7.
Then, the pyridinium salt B was excited into
[
[
c]
radical D. Intermediate E was generated from methyl radical 6
and radical D. The radical F can be converted to α, ꢀ-unsatu-
rated carbonyl compound G in the presence of tert-butoxy radi-
cal 5. Subsequently, intermediate H was formed from azometh-
ine ylide C and α, ꢀ-unsaturated carbonyl compound G via a
d]
[
a] Reaction conditions: 1a (0. 5 mmol), 2a (0.5 mmol), iodine source, oxidant
and additive (4.0 equiv.) in DMSO (2.0 mL) at 120 °C for 12 h. [b] Isolated
yields. [c] At 110 °C. [d] At 130 °C.
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Scheme 2. Synthesis of indolizines under the optimum conditions. [a] Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), I
2
(0.5 mmol, 1.0 equiv.), 3a TBHP (70 %
in water, 6.0 mmol, 12.0 equiv.) and AcOH (2.0 mmol, 4.0 equiv.) in DMSO (4.0 mL) at 120 °C for 12 h. [b] Isolated yields.
1,3-dipolar cycloaddition reaction. Intermediate I was obtained
In conclusion, we have developed an I /TBHP-mediated
2
by removing pyridine from intermediate H. Finally, intermediate [2+1+1+1] cycloadditions/oxidative aromatization reactions for
I was easily oxidized to the desired product 4a.
the novel and simple direct construction of indolizines using
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Communication
Scheme 3. Control experiments.
Scheme 4. Possible mechanism.
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Communication
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Keywords: Heterocycles · Cycloaddition ·
Methylene source · Metal-free · Multicomponent reactions
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Received: December 7, 2019
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