Intramolecular oxidative rearrangement: I2/TBHP/DMSO-mediated metal free facile access to quinoxalinone derivatives

Article abstract of DOI:10.1016/j.tetlet.2021.153268

Iodine/TBHP/DMSO mediated oxidative rearrangement of 3-styrylquinoxalin-2(1H)-one led to the formation of 3-aroylquinoxalin-2(1H)-ones in good to high yields via Kornblum oxidation. This methodology proceeds under mild conditions via oxidative aryl migrat

Full text of DOI:10.1016/j.tetlet.2021.153268

Tetrahedron Letters 78 (2021) 153268
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Intramolecular oxidative rearrangement: I2/TBHP/DMSO-mediated
metal free facile access to quinoxalinone derivatives
⇑
Nancy Slathia, Annah Gupta, Kamal K. Kapoor
Department of Chemistry, University of Jammu, Jammu 180 006, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Iodine/TBHP/DMSO mediated oxidative rearrangement of 3-styrylquinoxalin-2(1H)-one led to the forma-
tion of 3-aroylquinoxalin-2(1H)-ones in good to high yields via Kornblum oxidation. This methodology
proceeds under mild conditions via oxidative aryl migration, followed by CAC bond cleavage and does
not make use of any metal.
Received 4 May 2021
Revised 13 June 2021
Accepted 2 July 2021
Available online 10 July 2021
Ó 2021 Elsevier Ltd. All rights reserved.
Keywords:
Iodine/TBHP/DMSO
Oxidative rearrangement
Aroylquinoxalinones
Kornblum oxidation
Styrylquinoxalinones
Quinoxalin-2(1H)-ones have attracted considerable attention
due to their diverse range of biological and pharmacological activ-
ities [1]. More importantly, several quinoxalinone containing com-
pounds have found use in human clinical testing (Fig. 1) [2].
Additionally, this scaffold has extensively been explored in organic
synthesis, materials science and pharmaceuticals [3]. Interestingly,
3-aroylquinoxalin-2(1H)-ones exhibit some novel biological prop-
erties such as pteridine reductase inhibition [4] and antitumor
action [5] as well as electronic properties in free radical photoini-
tiated polymerization processes [6] and fluorescence applications
[7]. Despite numerous applications in medicinal and material
chemistry of aroylquinoxalinones, there are relatively few methods
known for their preparation (Scheme 1). Oxidative dehydrobromi-
I2/TBHP catalytic system has drawn a field of intense interest on
account of splendid work for CAC, CAN, CAO and CAS bond forma-
tions [9]. Also, Iodine/DMSO in combination with TBHP has
become an influential tool for the oxidation reactions of acetophe-
nones, 1,3-diketones,
a,b-unsaturated ketones, alkenes, and alky-
nes [10]. I2/TBHP/DMSO system has been used for the oxidative
rearrangement of
tones [11].
a,b-unsaturated diarylketones to 1,2-diaryl dike-
Recently, we synthesized styrylquinoxalinones using malonon-
itrile as activating agent [12]. We became interested to synthesize
aroylquinoxalinones from styrylquinoxalinones since, akin to
a,b-unsaturated diarylketones, the double bond in styrylquinoxali-
nones is polarized due to the presence of quinoxalinone. In contin-
uation to our interest in the synthesis of heterocyclic compounds
[13] and based on the strategy of Suryavanshi et al. [11] we
conceived the synthesis of aroylquinoxalinones from styrylquinox-
alinones (Scheme 1).
nation of 3-(a-bromobenzyl)quinoxalin-2(1H)-ones [8a], oxidative
ring contraction of 1,5-benzodiazepin-2-ones [8b], oxidative
coupling of quinoxalin-2(1H)-ones with arylaldehydes [8c] and
decarboxylative acylation of quinoxalin-2(1H)-ones with
a-oxo-
carboxylic acids [8d] have been reported so far. Recently, this scaf-
fold has been prepared by direct CAH acylation of quinoxalin-2
(1H)-ones with a-oxocarboxylic acids promoted by PIDA in visible
light [8e] and PIDA under thermal conditions [8f]. In addition, acy-
lation of quinoxalin-2(1H)-ones with benzaldehydes using eosin Y
as photocatalyst [8g] and aerobic benzylic oxidation of 3-ben-
zylquinoxalin-2-ol mediated by activated carbon has also been
reported [8h].
Initially, we started our investigation with (E)-3-styrylquinox-
alin-2(1H)-one 1a as a model substrate with I2 (0.5 eq), TBHP
(1 eq) and DMSO (2 ml) at room temperature stirring to realize
the formation of desired product in 40% yield (Table 1 entry 1).
To improve the yields of product, a preliminary set of reaction
between 1a and I2/TBHP/DMSO under different conditions has
been carried out (Table 1 entry 2–9) and the optimal conditions
for the reaction turned out to be the reaction of (E)-3-styrylquinox-
alin-2(1H)-one 1a (1 eq.) with I2 (1 eq.) and TBHP (3 eq.) in DMSO
at 90 °C (Table 1 entry 5). The effects of different solvents and
⇑
Corresponding author.
E-mail address: k2kapoor@yahoo.com (K.K. Kapoor).
https://doi.org/10.1016/j.tetlet.2021.153268
0040-4039/Ó 2021 Elsevier Ltd. All rights reserved.

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
Fig. 1. Few significant quinoxalinone containing compounds.
reaction temperature on the yields of desired product have also
subsequently been examined (Table 1).
of formyl radical, which gets by quenched by an in situ generated
hydroxyl radical from TBHP.
Furthermore, to establish the plausible reaction mechanism,
controlled experiments were performed. And it was observed that
all the three ingredients viz I2, TBHP and DMSO are needed for the
success of reaction (Scheme 2). The reaction was also performed in
presence of TEMPO (2 eq) and it was noticed that no product for-
mation occurred revealing thereby the radical nature of the
reaction.
Based on the aforementioned observations and the mechanism
proposed by Suryavanshi et. al.,11 the mechanism proposed is
shown in Scheme 3. [11]. In the beginning, iodine reacts with
With established reaction conditions, we investigated the sub-
strate scope of this reaction (Scheme 4). Most styrylquinoxalin-2
(1H)-ones tested delivered the corresponding products in good to
excellent yields under the optimal reaction conditions. Substrates
with the electron-donating groups afforded the desired products
(2b, 2c, 2d, 2e, 2f and 2g) in higher yields as compared to the sub-
strates with the electron-withdrawing group. The reaction also
occurred smoothly in presence of thiophene (2l) and pyridine
(2m).
Moreover, with styrylquinolines (Scheme 5), it was observed that
reaction took more time for completion and it can be attributed to
due to the low nucleophilicity of quinoline vis-à-vis quinoxalinone.
In conclusion, we have demonstrated an efficient, metal-free
and greener protocol for the synthesis of substituted 3-
aroylquinoxalin-2(1H)-ones. Reactions were carried out using
reagents I2, co-oxidant TBHP and DMSO via oxidative aryl migra-
tion followed by CAC bond cleavage under mild conditions. The
protocol is simple, economical and better yielding.
styrylquinoxalin-2(1H)-one to form iodonium intermediate
A
[13d]. The tertiary butyl peroxide radical (generated in situfrom
TBHP) undergoes 1,4-addition across intermediate A to furnish B.
Afterwards, intermediate B undergoes Kornblum oxidation in pres-
ence of DMSO to generate compound Cwith the elimination of
dimethyl sulfide and HI. Consequently, homolytic cleavage of
intermediate C provides D. Ultimately, a radical rearrangement of
intermediate D generates the desired product 2a with the removal
2

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
Scheme 1. Literature reports and present method for the synthesis of 3-aroylquinoxalin-2(1H)-ones.
3

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
Table 1
Optimization of reaction conditions for the synthesis of compound 2a.
Entry
Iodine (eq.)
TBHP (eq.)
Solvent
Temp. (oC)
Yield (%)a
1.
2.
3.
4.
5.
6.
7.
8.
9.
0.5
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
1.0
2.0
3.0
3.0
3.0
3.0
3.0
DMSO
DMSO
DMSO
DMSO
DMSO
CH3CN
DMF
RT
RT
90
90
90
90
90
90
90
40
50
60
75
90
NR
NR
NR
NR
MeOH
CHCl3
a
Isolated yield.
Scheme 2. Controlled experiments performed to establish reaction pathway.
4

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
Scheme 3. Plausible reaction pathway for the synthesis of 3-aroylquinoxalin-2(1H)-one.
5

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
Scheme 4. Substrate scope for the synthesis of 3-aroylquinoxalin-2(1H)-one.
Scheme 5. Synthesis of (4-chlorophenyl)(quinolin-2-yl)methanone from (E)-2-styrylquinoline.
6

N. Slathia, A. Gupta and K.K. Kapoor
Tetrahedron Letters 78 (2021) 153268
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The authors declare that they have no known competing finan-
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