Quinacetophenone: A simple precursor for synthesis of phenoxazines

Article abstract of DOI:10.1039/c9nj03525g

Quinacetophenone is a versatile and easy accessible building block for synthesis of various biologically active heterocyclic compounds. The inherent chemical reactivity of quinacetophenone has been hitherto utilized to construct various privileged organic molecules such as chalcones, chromones, flavonoids, coumarins and azoles etc. Herein we present an operationally simple method of synthesis of phenoxazines from quinacetophenone and anilines that exploits the inherent chemical reactivity of quinacetophenone. ESI-MS was used as a tool to establish the most plausible reaction mechanism.

Full text of DOI:10.1039/c9nj03525g

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DOI: 10.1039/C9NJ03525G
Quinacetophenone: A Simple Precursor for Synthesis of
Phenoxazines
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Saiprasad N. Nunewar,† Bhavana B. Muthyala,† Sowmya Dastari,† and Neelima D. Tangellamudi,*†
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†Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research, Hyderabad 500037;
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Abstract
Quinacetophenone is a versatile and easy accessible building block for synthesis of various biologically
active heterocyclic compounds. The inherent chemical reactivity of quinacetophenone has been hitherto
utilized to construct various privileged organic molecules such as chalcones, chromones, flavonoids,
coumarinsand azoles etc. Herein we present an operationally simple method of synthesis of
phenoxazines from quinacetophenone and anilines, that exploits the inherent chemical reactivity of
quinacetophenone. ESI-MS was used as a tool to establish the most plausible reaction mechanism.
Keywords: quinacetophenone, nucleophile, phenoxazine, aza-Michael attack, ESI-MS
Introduction
Quinacetophenone (2,5-dihydroxyacetophenone) is an easily accessible and widely used precursor for
the syntheses of flavonoids and alkaloids [1] and different medicinally active compounds [2].
Quinacetophenone has an inherent chemical reactivity in the hydroxyl, methyl ketone, carbonyl, and
aromatic moieties, thus affording privileged motifs of various kinds viz., chalcones, chromones,
flavonoids, coumarins, aurones, phenazines and azoles (Scheme 1) [3]. Quinacetophenone has also been
used to synthesize various potential synthetic precursors, which have been utilized in the synthesis of
novel and complex heterocyclic compounds [4].
Quinacetophenone can be found in several synthetic methodologies toward potential organic molecules
and can be synthesized from benzoquinone by Friedel–Crafts acetylation followed by Fries-
rearrangement or Hoesh reaction [5]. Thus, quinacetophenone is a simple and economically available
building block that can afford diverse and advantageous medicinally active privileged motifs.
Quinacetophenone is important from the viewpoints of both synthesis and chemical reactivity. The
superposition of hydroquinone structure and the 2-hydroxyacetophenone structure with its α-hydroxy o-
quinone methide tautomer imparts rich chemistry to quinacetophenone. The 1-acetyl group is also
known for its high reactivity which could be attributed to proton donation to the carbonyl group from
the adjacent 2-hydroxy group and resonance of the carbonyl group with the aromatic ring (Figure 1) [6,
7].
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1
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Previous work on quinacetophenone
3
4
N
5
HO
N
6
7
8
O
OH
OH
phenazine
Takabatake et al., 2000
O
HO
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O
N
coumarin
Neelakantan et al., 1982
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HN
OH
HO
diazole
Fullam et al., 2013
OH
OH
O
OH
HO
HN
O
OH
O
chromene
HO
Desai and Mavani, 1947
indole
Sharma et al., 1983
O
O
aurone
Zhao et al., 2011
This work
H
G
N
O
OH
G
G
HO
N
H
HO
O
NH2
O
MnO2, toluene,
rt, 10h
phenoxazine
Scheme 1: Synthesis of various privileged motifs from quinacetophenone
OH
HO
O
quinacetophenone
OH
OH
O
O
H
H
O
O
Figure 1. Proton donation and high reactivity of 1-acetyl group of quinacetophenone
In the presence of various oxidants, quinacetophenone is oxidized to give 2-acetyl-[1,4]-benzoquinone
A, which is not isolable but immediately converted further. Most prominently, nucleophiles attack
selectively at C-6 providing 6-substituted quinacetophenone, probably driven by the resonance
stabilization associated with the intermediate B is as shown in figure 2 [8].
O
O
OH
Nu
Nu-
Nu
O
O
HO
O
HO
O
A
B
Q
Figure 2. 2-acetyl 1,4- benzoquinone (A); Intermediate (B) 6-substituted quinacetophenone (Q)
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Phenoxazines have been studied intensively as an important heterocyclic system for the synthesis of
herbicides, fungicides, and therapeutically usable drugs [9a,9b]. Phenoxazine is a pharmacophore in
several drugs owing to their anti-inflammatory,[10] antihistaminic,[11] antimicrobial,[12,13] and
antitubercular properties. [14] Phenoxazine derivatives and polymers have also attracted much attention
for their industrial utility as dye-based solar cells,[14,15] indicators,[16,17] retardants for
polymerization, anti-fluorescent material and biological stains[18].
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9
Several benzoxazine derivatives are currently in the development phase as potential new drugs[9c].
Dactinomycin is an antibiotic produced by Streptomyces parvullus, used in malignant neoplasms
(Figure 3).
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F
F
CN
OH
NH2
O
O
CN
K2CO3
(a)
+
DMF, 130 °C, 9h
N
H
NHAc
R2
O
N
K2CO3/ DMEDA
R1
R2
(b) R1
toluene, 135 °C, 24h
I
Ac
Br
O
R3-NH2
O
R2
(c) R1
R2
R1
Pd(OAc)2, DPEPhos
t-BuONa
toluene, 120 °C, 15h
N
Br
R3
HO
I
B(OH)2
NHAc
NHAc
NHAc
I
MeO
O
(d)
I BF4
m-CPBA
BF3.Et2O
CH2Cl2,
-78 °C
t-BuOK
toluene, rt
I
OMe
NHAc
NHAc
O
O
K2CO3/ DMEDA
toluene, 135 °C, 24h
NaOMe
MeOH, reflux
N
N
H
Ac
Scheme 2: Previously reported syntheses of phenoxazines
O
O
N
O
O
N
N
N
O
N
NH
O
O
N
O
O
O
NH
HN
HO
O
HN
O
O
OH
O
O
N
N
O
N
NH2
O
O
O
Dactinomycin
Anti-cancer agent
Pirenoxine
Anti-inflammatory agent
Figure 3: Marketeddrugs containing phenoxazine
Dactinomycin contains a phenoxazine ring which is bound to two cyclic pentapeptides. The
phenoxazine ring of Dactinomycin is known to intercalate into DNA, thus inhibiting DNA-dependent
RNA polymerase I, displaying antitumor activity. It also inhibits RNA synthesis (transcription), by
binding to DNA. Pirenoxine is an anti-cataract agent, used for the topical treatment of ophthalmic
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inflammatory conditions such as corneal and conjunctival inflammations, uveitis, and ocular-odema
(Figure 3).
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Because of its commercial and biological importance, various synthetic procedures have been put
forward, most of which are also summarized in a recent review [19, 20]. Ever since the first synthesis of
phenoxazine that dates back more than 100 years [21a], a range of synthetic routes to this privileged
scaffold has been developed [21b]. Transition metal-free routes include the synthesis from 2-
aminophenols and 3,4-dihaloarenes decorated with electron-withdrawing substituents, which proceed
through a Smiles rearrangement (Scheme 2a) [22-24].
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Most of the routes either use aminophenol as the substrate or require o-halo phenols for C-N bond
formation. Recently, Bolm and co-workers reported a metal-free cyclization of iodo-substituted diaryl
ethers with a broad substrate scope (Scheme 2b) [25]. Transition metal-catalyzed C–O and C–N cross
couplings have also been reported, e.g., Cu-catalyzed cyclization of 2-(2-bromophenoxy) anilines [24,
26, 27]. A Pd-catalyzed double N-arylation using di(2-bromoaryl) ethers and primary amines (Scheme
2c) [28]. A transition metal-free formal synthesis of phenoxazine was also presented using an o-
disubstituted diaryl ether prepared by o-arylation of a phenol with an unsymmetrical diaryliodonium
salt which was cyclized to acetylphenoxazine (Scheme 2d) [29, 19].
Our group has been particularly involved in research that aims to develop privileged scaffolds by one-
pot syntheses [30].Thus encouraged by the aforementioned utility of quinacetophenone combined with
the rationale mentioned above, we have surmised that phenoxazines can be constructed from
quinacetophenone and anilines. We have presumed that the anilines can attack at C-6 position with the
primary amine moiety and eventually cyclize to form phenoxazines C, in a way similar to the formation
of benzoxazoles in our previous report [30] (figure 4).
G
O
O
O
G
NH2
G
N
H
O
O
N
H
HO
HO
O
O
A
B-I
C
Figure 4. Attack of amino group at the C-6 position of 2-acetyl 1,4- benzoquinone (A); to form Intermediate (B-I) which cyclizes to a
phenoxazine (C)
Results and Discussion
A methodology was designed for the synthesis of phenoxazines in one-pot protocol from
quinacetophenone and substituted anilines in the presence of manganese dioxide as an oxidizing agent.
We have selected quinacetophenone I and aniline II as model substrates to validate the methodology.
Quinacetophenone was initially transformed to a transient quinone in the presence of manganese
dioxide ( as monitored by TLC, for a change in the nature of the spot) and aniline was added and stirred
at room temperature for three hours. We have observed a surprise formation of two phenoxazines 3-
substituted phenoxazine 1D and simple phenoxazine 1C. The results of the optimization of reaction
conditions are shown in Table 1. Initially, the effect of different oxidants was evaluated. No desired
product was observed when the reaction was performed in the absence of an oxidant.
Among the various oxidants examined, manganese dioxide was the most suitable for the reaction, giving
the corresponding phenoxazines 1D in 62% yields. We have previously used silver oxide as an oxidant
4

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for the synthesis of benzoxazoles [9]. However, the silver oxide was found to be ineffective in the
present reaction, as it afforded the product in only a 20% yield. Further screening of the solvents
indicated that toluene afforded the product in best yields and use of Dichloromethane, Chloroform,
THF, Dioxane and Dichloroethane (entries 5, 7, 9, 12, 13) resulted in lower yields. Among the various
oxidants tested, like Silver oxide, Manganese dioxide, Diacetoxy-iodobenzene, and Lead acetate
(entries 4, 6, 12, 15) Manganese dioxide afforded 1D in 62% yield.
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Finally, the influence of the temperature on the reaction was also examined. Increasing the reaction
temperature from rt to reflux conditions lead to a decrease in yields. Thus Manganese dioxide in
Toluene at room temperature was chosen as the suitable reaction condition. With the optimized reaction
conditions in hand (Table 1, entry 6), the scope and limitations of the novel heterocyclization of
various anilines were examined (Table 2).
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Table 1: Optimization of reaction conditionsa
H
OH
O
N
O
+
Conditions
+
HO
HO
N
H
HO
N
H
NH2
O
O
O
II
I
1C
1D
S.
No.
1
Oxidant
Solvent
CH2Cl2
Temp.
(oC)
r.t.
Yieldb
15%
Ag2O
2
3
4
Ag2O
Ag2O
Ag2O
CH2Cl2
DCE
Toluene Reflux
Reflux
r.t.
18%
30%
20%
5
6
7
MnO2
MnO2
MnO2
CH2Cl2
r.t.
r.t.
r.t.
22%
62%
28%
Toluene
CHCl3
8
9
MnO2
MnO2
Toluene Reflux
30%
10%
THF
r.t.
10
11
12
13
14
15
16
DiacetoxyIodobenzene
DiacetoxyIodobenzene
DiacetoxyIodobenzene
DiacetoxyIodobenzene
Pb(OAc)2
CHCl3
Toluene
Dioxane
DCE
CHCl3
Toluene
Toluene
Reflux
Reflux
Reflux
Reflux
r.t.
15%
33%
38%
34%
9%
Pb(OAc)2
Pb(OAc)2
r.t.
r.t.
12%
-
[a] Reaction conditions: Quinacetophenone I (1.0 mmol), Aniline II (1.0 mmol), Oxidant (10.0 mmol), solvent (10 mL). [b] yield of the
pure and isolated major products. The isolated yield for 1C was 20%.
Table 2. One step synthesis of phenoxazine hybrids from quinacetophenone and substituted anilines
H
OH
O
N
O
G
MnO2
G
+
G
G
HO
+
HO
N
H
Toluene, r.t., 10h
HO
N
H
NH2
II
O
O
O
5
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C
D

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Entry
1
-G
H
Product
Yield (D)
60c
H
N
O
5
6
HO
N
H
O
O
7
8
9
1D
2D
H
N
2
3
4-CH3
62
O
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45
46
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49
50
51
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58
59
60
HO
N
H
2-OMe
50
O
H
N
O
HO
N
H
O
O
O
3D
4D
H
N
4
5
4-F
50
48
O
F
F
HO
N
H
Br
2-Br
H
N
O
HO
N
H
Br
O
O
5D
6D
H
N
6
7
3-CF3
3-iPr
61
54
F3C
O
HO
N
H
CF3
H
N
O
HO
N
H
O
7D
8D
H
N
8
9
3-Br
2-F
43
49
Br
O
HO
N
H
Br
O
F
H
N
O
HO
N
H
F
O
9D
10
4-iPr
58
H
N
O
HO
N
H
O
10D
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H
11
12
13
14
4-Br
3-Cl
52
50
55
53
N
O
Br
1
2
3
4
5
6
7
8
Br
Cl
HO
N
H
O
11D
H
N
O
HO
N
H
Cl
Cl
O
12D
9
10
11
12
13
14
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H
N
4-Cl
O
Cl
HO
N
H
O
13D
H
N
4-CF3
O
CF3
F3C
HO
N
H
O
14D
H
N
15
3-OMe
48
O
O
HO
N
H
O
O
15D
c = C was isolated and characterized only for 1.
In order to establish the most plausible mechanism, we have made ESI-MS spectrometry as techniques
of our choice, as NMR spectroscopy alone was useful only in validating the products formed. Figure
5a-5c shows the mass spectra of the reaction at different intervals. We have captured reaction
intermediates by spectroscopic techniques and established the most probable reaction pathway.
In general, because of the low concentration and transient nature of most of the intermediates involved,
their identification has remained a task of great complexity and the information provided was limited
except in the case of products. For example, it was impossible to obtain the molecular ion peak for 1-
acetyl benzoquinone formed after the addition of MnO2 to quinacetophenone. However, 1 min
following the addition of aniline, the presence of a prominent peak at m/z 244.0972 amu [B-I + H]+ in
Figure 5a provided key information on the composition of intermediate B-I, thus allowing the
intermediate to be associated with the formation of the aza-Michel addition product for the eventual
formation of the desired product.
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1
2
3
O
4
5
O
HO
N
H
6
7
8
9
O
HO
(
N
H
+
C + Na
(
) : 264.0638
O
+
C + H
) : 242.0818
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O
O
N
H
H
HO
+
B-I + H
(
) : 244.0972
Figure 5a i: ESI-MS of the reaction of I with 1 equiv of aniline II 1 min after the addition of II. The signals due to species [B-I + H] + and
[C + H] + are encircled
H
N
O
HO
N
H
O
+
D + H
(
) : 333.1240
Figure 5a ii: ESI-MS of the reaction of I with 1 equiv of aniline II 1 min after the addition of II (m/z 320-350). The signal due to species [D
+ H] + are encircled
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1
2
3
4
O
5
6
7
8
HO
N
H
O
+
O
C + Na
(
) : 264.0638
9
HO
(
N
H
10
11
12
13
14
15
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O
+
C + H
) : 242.0818
O
O
N
H
H
HO
+
B-I + H
(
) : 244.0972
Figure 5b i: ESI-MS of the reaction of I with 1 equiv of aniline II 30 min after the addition of II. The signals due to species [B-I + H] +and
[C + H] + are encircled
H
N
O
HO
N
H
O
+
D + H
(
) : 333.1240
Figure 5b ii: ESI-MS of the reaction of I with 1 equiv of aniline II 30 min after the addition of II. The signals due to species [D + H] +
encircled
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1
2
3
4
5
6
7
O
8
9
HO
(
N
H
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11
12
13
14
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60
O
+
C + H
) : 242.0818
O
O
N
H
H
HO
+
B-I + H
(
) : 244.0972
Figure 5c i: ESI-MS of the reaction of I with 1 equiv of aniline II 3h after the addition of II. The signals due to species [B-I + H] + and [C
+ H] + are encircled
H
N
O
HO
N
H
O
+
D + H
(
) : 333.1240
Figure 5c ii: ESI-MS of the reaction of I with 1 equiv of aniline II 3h after the addition of II. The signals due to species [D + H] + encircled
+
The peak at m/z 244.0972 amu [B-I + H]
coexists with the second molecular ion peak at m/z
242.0818 amu corresponding to C which is indicative of its rapid cyclization to phenoxazine C in
accordance with the mechanism proposed in Scheme 2 (Figure 5a i). Further, the arising of the small
peak at m/z 333.1240 amu may be indicative of the beginning of the formation of D (Figure 5a ii). The
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1
monitoring of the reaction by H NMR spectroscopy was useful for the products. The initial
phenoxazine C, characterized by H NMR and other spectroscopic techniques, was obtained as the
1
1
2
3
minor product in the reactions with aniline (Table 2).
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The ESI-MS of the reaction mixture after 30 min showed the increasing intensity of the peak at m/z
333.1236 amu corresponding to [D + H],+ and decreasing intensity of peak at m/z 244.0968 amu
+
corresponding to [B-I + H] as the reaction progressed forward (figure 5b i and 5b ii). Similarly, the
ESI-MS at 3h also showed increasing intensity of the peak at m/z 333.1241 amu corresponding to [D +
+
+
H] and decreasing intensity of peak at m/z 244.0962 amu corresponding to [B-I +H] in accordance
with the progression of the reaction towards completion (Figure 5c i and 5c ii).
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There are peaks detected by ESI-MS, which may be species that may have been formed during the
ionization process and may be slightly different from the true species present in the reaction.
O
H
OH
MnO2
O
O
N
G
G
O
N
H
H
HO
O
O
HO
G
B-I
C14H13NO3
O
O
A
H O
H2N
Exact Mass: 243.09
H
NH2
H
O
O
N
O
G
G
G
G
G
HO
N
H
O
N
H
O
N
MnO2
H
O
O
O
E
C
C20H16N2O3
Exact Mass: 332.12
H
C14H11NO3
Exact Mass: 241.07
N
O
G
G
HO
N
H
O
D
C20H16N2O3
Exact Mass: 332.12
Scheme 3: The most plausible reaction mechanism envisaged for the reaction based on ESI-MS studies
at regular intervals during the reaction
Thus, based on the nature of the intermediate captured by ESI-MS, we have envisioned the most
plausible mechanistic pathway for the reaction (Scheme 3). The initial event may be considered as the
nucleophilic attack of amine in a Michael fashion on the transient enone A to generate an intermediate
B-I (see also, figure 2). Intermediate B-I may undergo electrocyclization and further rearomatization to
phenoxazine C. The phenoxazine C undergoes oxidation in the presence of MnO2 and undergoes a
second Michael attack by aniline to form an intermediate E. E further rearomatizes to the final product
D. Electrocyclization of D could be improbable due to proton donation to the carbonyl group from the
adjacent 2-hydroxy group and resonance of the carbonyl group with the aromatic ring (also see figure 1)
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Conclusion
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In conclusion, we have demonstrated the utility of the versatile, easily accessible building block
quinacetophenone, for the synthesis of phenoxazines via C-N formation as a key step.
Quinacetophenone has been hitherto used in the synthesis of novel and complex heterocyclic
compounds including coumarins, chromones, azoles, aurones, and phenazines, etc. ESI-MS was used as
a tool to study the most plausible mechanism of the reaction. The yields are moderate, the substrate
scope of the strategy is wide and tolerant of various electron donating and electron withdrawing groups.
The biological studies for the newly synthesized phenoxazines are underway. Overall, our study
suggests that owing to the presence and positioning of the phenol and ketone functionalities,
quinacetophenone could be an attractive precursor in organic synthesis and the method presented here is
a modular protocol that can be adopted for synthesizing various other useful privileged scaffolds.
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Experimental Section
General Methods: All reactions were carried out under an inert atmosphere with dry solvents unless
otherwise stated. Reactions were monitored by thin layer chromatography (TLC) on silica gel plates (60
F254), using UV light detection. Visualization of the spots on TLC plates was achieved either by UV
light or by staining the plates in 2, 4-Dinitro phenyl hydrazine/ Ninhydrin stains and charring on a hot
plate. Flash chromatography was performed on silica gel (200-400 mesh) using distilled hexane, ethyl
1
acetate, dichloromethane. H NMR and 13C NMR spectra were recorded in CDCl3 solution by using
Bruker 500 MHz NMR spectrometer. Chemical shifts are reported as δ values relative to internal CDCl3
δ 7.26 or TMS δ 0.0, DMSO-d6 δ 2.5 for 1H NMR and CDCl3 δ 77.0, DMSO-d6 δ 39.52 for 13C NMR.
1H NMR data were recorded as follows: chemical shift [multiplicity, coupling constant(s) J (Hz),
relative integral] where multiplicity is defined as s (singlet), d (doublet), t (triplet), q (quartet), dd
(doublet of doublet), m (multiplet), bs (broad singlet). FT-IR spectra were recorded on PerkinElmer
spectrometer. High-resolution mass spectra (HR-MS) [ESI+] were obtained using Agilent Q-TOF mass
spectrometer 6540 series instrument.
General procedure for the synthesis of 1-15: A suspension of quinacetophenone I (1 mmol) and
MnO2 (0.860g, 10 mmol) is cooled in an ice bath to 0 °C under constant stirring. Anilines (1 mmol) in
anhydrous toluene was added and stirred at rt for 10h. The mixture was filtered through celite and
washed with toluene. Removal of the solvent under reduced pressure followed by column
chromatography (5% EtOAc/Hexane) yielded pure 1-(indol-2-yl)-phenoxazine hybrids.
Supporting Information is available free of charge: experimental procedures, characterization of all
new products, copies of 1H NMR, and 13C NMR spectra.
Corresponding Author
* neelima@niperhyd.ac.in
Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval to the
final version of the manuscript.
Acknowledgments
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The authors are thankful to NIPER Hyderabad for facilities and Department of Science and Technology
for the financial support (DST-File No: SB/S1/OC-55/2013).
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References
1. (a) A. Fougerousse, E. Gonzalez and R. Brouillard, J. Org. Chem., 2000, 65, 583–586. (b) S.
Ruchirawat and T. Mutarapat, Tetrahedron Lett., 2001, 42, 1205–1208. (c) J. N. Kim, Y. J. Im
and J. M. Kim, Tetrahedron Lett., 2002, 43, 6597–6600.
2. (a) M. Cushman, H. Zhu, R. L. Geahlen and A. J. Kraker, J. Med. Chem., 1994, 37, 3353–3362.
(b) S. I. El-Desoky, F. A. Badria, M. A. Abozeid, E. A. Kandeel and A. H. Abdel-Rahman, Med
Chem Res, 2013, 22, 2105–2114. (c) U. Gerlach, J. Brendel, H.-J. Lang, E. F. Paulus, K.
Weidmann, A. Brüggemann, A. E. Busch, H. Suessbrich, M. Bleich and R. Greger, J. Med.
Chem., 2001, 44, 3831–3837.
3. (a) F. T. Mujica, H, Buchholz, C. Carola, W. Rautenberg, C. Sirrenberg, Patent EP (2004)
Application no. 1426372. (b) R.D. Desai, C.K. Mavani, Proc. – Indian Acad. Sci. Sect.A, 1947,
25, 353–358. (c) T. Takabatake, T. Miyazawa and M. Kojo, Heterocycles, 2000, 53, 2151–
2162. (d) E. Fullam, J. Talbot, A. Abuhammed, I. Westwood, S. G. Davies, A. J. Russell and E.
Sim, Bioorg. Med. Chem. Lett., 2013, 23, 2759–2764. (e) H. R. Park, K.-S. Park and Y. Chong,
Bioorg. Med. Chem. Lett., 2011, 21, 3202–3205. (f) W. Zhao, J. Sun, H. Xiang, Y. Zeng, X. Li,
H. Xiao, D. Chen and R. Ma, Bioorg. Med. Chem., 2011, 19, 3192–3203. (g) S.C. Sharma,
M.P., Swami, R.C. Sharma, J. Indian Chem. Soc. 1983, 60, 1002–1004. (h) S. K. De and R. A.
Gibbs, Synthesis, 2005, 2005, 1231–1233. (i) S. Neelakantan, P.V. Raman, A. Tinabaye, Indian
J. Chem. Sect. B 1982, 21, 256–267. (j) G. Roma, M. Di Braccio, G. Grossi, D. Piras, G.
Leoncini, D. Bruzzese, M. G. Signorello, P. Fossa and L. Mosti, J. Med. Chem., 2007, 50,
2886–2895.
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4. (a) M. H. Ali, M. Niedbalski, G. Bohnert and D. Bryant, Synth. Commun., 2006, 36, 1751–
1759. (b) A. H. Abdel-Rahman, M. A. A. Hammouda and S. I. El-Desoky, Heteroatom Chem.,
2005, 16, 20–27. (c) S. I. El‐Desoky, M. A. Abozeid, E. A. Kandeel and A. H. Abdel‐Rahman,
Journal of Heterocyclic Chemistry, 2014, 51, 1270–1276.
5. (a) H. Naeimi and L. Moradi, BCSJ, 2005, 78, 284–287. (b) H. Naeimi and L. Moradi, Russ J
Org Chem, 2007, 43, 1757. (c) M. L. Hari Kumaran Nair and L. Shamla, Journal of the Indian
Chemical Society, 2009, 86, 913–919. (d) H. Sharghi and B. Kaboudin, Journal of Chemical
Research-s - J CHEM RES-S, 1998, 628–629.
6. (a) S. Sharma, S.C. M. P. and Sharma, R.C., J. Indian Chem. Soc, 1983, 60, 1002–1004. (b)
Hosoya, Takashi, D. French, Alfred and Rosenau, Thomas, Mini-Reviews in Organic
Chemistary, 2015, 12, 88–95.
7. (a) E. M. Mmutlane, J. P. Michael, I. R. Green and C. B. de Koning, Org. Biomol. Chem., 2004,
2, 2461–2470. (b) J.-L. Fillaut, J. Andriès, R. D. Marwaha, P.-H. Lanoë, O. Lohio, L. Toupet
and J. A. Gareth Williams, Journal of Organometallic Chemistry, 2008, 693, 228–234. (c) J. R.
Mays, S. A. Hill, J. T. Moyers and B. S. J. Blagg, Bioorg. Med. Chem., 2010, 18, 249–266.
8. (a) P. Capdevielle and M. Maumy, Tetrahedron, 2001, 57, 379–384. (b) O. Prakash, R. Pundeer
and H. Kaur, Synthesis, 2003, 2003, 2768–2770. (c) H. R. Park, K.-S. Park and Y. Chong,
Bioorg. Med. Chem. Lett., 2011, 21, 3202–3205. (d) M. H. Ali, M. Niedbalski, G. Bohnert and
D. Bryant, Synth. Commun., 2006, 36, 1751–1759.
9. (a) N. Zidar and D. Kikelj, Tetrahedron, 2008, 64, 5756–5761. (b) T. Kurz, Tetrahedron, 2005,
61, 3091–3096. (c) Nadeem Siddiqui, Ruhi Ali, M. Shamsher Alam and Waquar Ahsan, J.
Chem. Pharm. Res., 2010, 2, 309–316.
13

New Journal of Chemistry
Page 14 of 15
View Article Online
DOI: 10.1039/C9NJ03525G
10. E. M. Odin, P. K. Onojah, L. E. S. Akpanisi and B. O. Akabueze, Chemical Science
International Journal, 2016, 1–12.
11. K. Kohno, M. Miyake, O. Sano, M. Tanaka-Kataoka, S. Yamamoto, S. Koya-Miyata, N. Arai,
M. Fujii, H. Watanabe, S. Ushio, K. Iwaki and S. Fukuda, Biological and Pharmaceutical
Bulletin, 2008, 31, 1938–1945.
12. P. Kohli, S. K. Srivastava, S. D. Srivastava, J. Appl. Chem. 2014, 3 (2), 525–534.
13. S. Shimizu, M. Suzuki, A. Tomoda, S. Arai, H. Taguchi, T. Hanawa and S. Kamiya, The
Tohoku Journal of Experimental Medicine, 2004, 203, 47–52.
14. M. Anil Reddy, B. Vinayak, T. Suresh, S. Niveditha, K. Bhanuprakash, S. Prakash Singh, A.
Islam, L. Han and M. Chandrasekharam, Synth. Met., 2014, 195, 208–216.
15. M. Karlsson, L. Yang, M. K. Karlsson, L. Sun, G. Boschloo and A. Hagfeldt, Journal of
Photochemistry and Photobiology A: Chemistry, 2012, 239, 55–59.
16. M. Ionescu and H. Mantsch, in Advances in Heterocyclic Chemistry, eds. A. R. Katritzky and
A. J. Boulton, Academic Press, 1967, vol. 8, pp. 83–113.
17. M. Miyake, S. Yamamoto, O. Sano, M. Fujii, K. Kohno, S. Ushio, K. Iwaki, S. Fukuda,
Bioscience, Biotechnology, and Biochemistry, 2010, 74, 753–758.
18. J. Jose and K. Burgess, Tetrahedron, 2006, 62, 11021–11037.
19. G. Kervefors, A. Becker, C. Dey and B. Olofsson, Beilstein J. Org. Chem., 2018, 14, 1491–
1497.
20. Shruti, J. Dwivedi, D. Kishore and S. Sain, Synth. Commun., 2018, 48, 1377–1402.
21. (a) A. Bernthsen, Berichte der deutschen chemischen Gesellschaft, 1887, 20, 942–944. (b) S.
Katsamakas, A. L. Zografos and V. Sarli, Curr. Med. Chem., 2016, 23, 2972–2999.
22. G. C. Eastmond, T. L. Gilchrist, J. Paprotny and A. Steiner, New J. Chem., 2001, 25, 385–390.
23. D. M. Schmidt and G. E. Bonvicino, J. Org. Chem., 1984, 49, 1664–1666.
24. G. E. Bonvicino, L. H. YogodzinskiI, R. A. Hardy, J. Org. Chem., 1961, 26, 2797–2803.
25. I. Thomé and C. Bolm, Org. Lett., 2012, 14, 1892–1895.
26. N. Liu, B. Wang, W. Chen, C. Liu, X. Wang and Y. Hu, RSC Adv., 2014, 4, 51133–51139.
27. G. B. Eregowda, H. N. Kalpana, R. Hegde and K. N. Thimmaiah, IJC-B Vol.39B (04) [April
2000].
28. L. Zhang, X. Huang, S. Zhen, J. Zhao, H. Li, B. Yuan and G. Yang, Org. Biomol. Chem., 2017,
15, 6306–6309.
29. M.-L. Louillat‐Habermeyer, R. Jin and F. W. Patureau, Angew. Chem. Int. Ed., 2015, 54, 4102–
4104.
30. (a) J. Iqbal, N. D. Tangellamudi, B. Dulla and S. Balasubramanian, Org. Lett., 2012, 14, 552–
555. (b) N. D. Tangellamudi, S. B. Shinde, V. Pooladanda, C. Godugu and S. Balasubramanian,
Bioorg. Med. Chem. Lett., 2018, 28, 3639–3647.
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32
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34
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36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
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Quinacetophenone: A Simple Precursor for Synthesis of
Phenoxazines
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Saiprasad N. Nunewar, † Bhavana B. Muthyala, † Sowmya Dastari† and Neelima D.
Tangellamudi *†
H
OH
N
O
O
G
MnO2 (10 eq)
G
+
G
+
G
HO
HO
N
H
HO
N
H
Toluene, rt, 10h
NH2
O
CH3
O
O
43-62% 15 examples
G= H, 4-CH3, 2-MeO, 4-F, 2-Br, 3-CF3, 3-iPr, 3-Br, 2-F, 4-iPr, 4-Br, 3-Cl,
4-Cl, 4-CF3, 3-MeO