Unexpected one pot C (aryl)-N bond cleavage and Questiomycin A formation from the reduction reaction of 2-amino-6-nitrophenol derivatives

Article abstract of DOI:10.1016/j.tetlet.2015.09.080

2-Amino-6-nitrophenol derivatives 5A and 5B have been prepared from the bromonitro phenol derivative 4 using the Buchwald conditions. While attempting one pot reduction of nitro group and deprotection of phenolic benzyl group of the compounds 5A and 5B separately using Pd/C in methanol under H₂ atmosphere, an unexpected C(aryl)-N bond cleavage reaction had occurred which was followed by formation of a known compound Questiomycin A (2-amino-3H-phenoxazin-3-one) 1 from both the compounds. In the present study, the danger of deamination of Buchwald products 5A and 5B under the conditions of catalytic hydrogenation and the simultaneous formation of phenoxazine 1 is disclosed.

Full text of DOI:10.1016/j.tetlet.2015.09.080

Tetrahedron Letters 56 (2015) 6104–6107
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Unexpected one pot C (aryl)–N bond cleavage and Questiomycin A
formation from the reduction reaction of 2-amino-6-nitrophenol
derivatives
⇑
Shaik Mustafa , K. Santhosh Reddy, M. S. Surendra Babu
Department of Chemistry, Gitam University, Hyderabad Campus, Telangana State, India
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 23 July 2015
Revised 16 September 2015
Accepted 19 September 2015
Available online 21 September 2015
2-Amino-6-nitrophenol derivatives 5A and 5B have been prepared from the bromonitro phenol
derivative 4 using the Buchwald conditions. While attempting one pot reduction of nitro group and
deprotection of phenolic benzyl group of the compounds 5A and 5B separately using Pd/C in methanol
under H2 atmosphere, an unexpected C(aryl)–N bond cleavage reaction had occurred which was followed
by formation of a known compound Questiomycin A (2-amino-3H-phenoxazin-3-one) 1 from both the
compounds. In the present study, the danger of deamination of Buchwald products 5A and 5B under
the conditions of catalytic hydrogenation and the simultaneous formation of phenoxazine 1 is disclosed.
Ó 2015 Elsevier Ltd. All rights reserved.
Keywords:
2-Aminophenol
Tricyclic compound
Buchwald reaction
2-Aminophenoxazin-3-one
Catalytic hydrogenation
Although significant progress has been made in the develop-
ment of catalytic aryl C–N bond formation and the synthesis of
Buchwald products,1 very few methods are available2 for the cat-
alytic cleavage of C(aryl)–N bonds of aniline derivatives. Recently
reductive deamination of o-acylaniline derivatives was achieved
by heating the reaction with the catalyst RuH2(CO)(PPh3)3.3 But
this method is applicable to limited substrates containing ortho
directing group. Further, cleavage of C(aryl)–N bonds requires
either expensive reagents2 or harsh conditions.3 Therefore, there
is a demand to develop methods for deamination reactions to pre-
pare important organic synthons. Herein we report one pot C
(aryl)–N bond cleavage (catalytic deamination) of two Buchwald
products 5A and 5B with Pd/C under the atmosphere of Hydrogen
in methanol followed by Questiomycin A formation.
Questiomycin A is the core structure of pharmaceutical active
compounds like actinomycin, Plectosphaeroic Acid A and cinna-
barinic acid. It belongs to the structural class of phenoxazine and
can be isolated from Streptomyces species and some fungi and mar-
ine bacteria Actinomadura sp.M048.4,5 It has been thoroughly
investigated for many bio activities like anticancer6 and antimicro-
bial.7 It is an antibiotic and is obtained from Penicillium expansum, a
resident fungal strain of the orbital complex Mir.8 It is weakly
active against bacteria, fungi, plants, and tumor cell lines, and
inhibits aromatase and sulfatases.4 Questiomycin, like other phe-
noxazines, stimulates cell growth and shows an ability to form
stable free radicals.9 Recently, Questiomycin A has been shown
to inhibit pulmonary metastasis caused by mouse melanoma
cells.10
Questiomycin A and its derivatives are usually prepared by
enzymatic oxidation of o-aminophenols using laccases and horse-
radish peroxidases11 and the chemical syntheses involve oxidation
of o-aminophenols catalyzed by TBHP/diphenyl diselenide,11 coba-
loxime(II) derivatives,12 Co(salen)13 or Mn–porphyrin complexes.14
Despite general chemical oxidative methods and enzymatic
methods for the synthesis of 2-amino-3H-phenoxazin-3-one from
2-aminophenol, to our knowledge only a reductive method15 is
available for the synthesis of Questiomycin A which is published
very recently. In this method authors used dissolving metal condi-
tions for the reduction of 2-nitrophenol derivatives. These condi-
tions are complicated and harsh in practice. The catalytic
hydrogenation conditions we have been reporting here are novel,
and performed at room temperature with easily available reagents.
Apart from the use of phenoxazine moieties as pharmaceuti-
cally active compounds, the derivatives of these compounds have
also been used widely in dye sensitized solar cells (DSSC).16–21
These simple moieties usually are known as competent laser dyes,
and have not been explored much as building blocks in current
small-molecule based light emitting diode materials.22 Several
phenoxazine derivatives have been prepared and used in the
function of emitting materials,23 semiconducting transistors and
⇑
Corresponding author. Tel.: +91 9703787968.
E-mail address: mustaff_02@yahoo.co.in (S. Mustafa).
http://dx.doi.org/10.1016/j.tetlet.2015.09.080
0040-4039/Ó 2015 Elsevier Ltd. All rights reserved.

S. Mustafa et al. / Tetrahedron Letters 56 (2015) 6104–6107
6105
Br
Br
O
N
OH
Br2
OH
OBn
NO2
Bn-Br, K2CO3
Acetone,r.t.
H
O
OH
HN
H
AcOH:H2O
(1:1)
O
N
O
NO2
O
NO2
HO
Hydride
shift
3
2
+
4
NH2
N
1
NH2
HO
13
HN
OBn
NO2
Pd2(dba)3, S-phos
Scheme 4.
Pd/C, H2
Methanol
Aniline, Cs2CO3
Toluene, reflux
5A
O
O
separately with aniline and piperidine under Buchwald conditions
using Pd2(dba)3, S-phos and Cs2CO3 in toluene at 110 °C to furnish
the Buchwald products 5A and 5B, respectively (Scheme 1). The
structure of the compound 5A was confirmed by its 1H NMR spec-
trum which showed characteristic peaks at d 5.64 (broad singlet)
4
N
NH2
N
1
Pd2(dba)3, S-phos
OBn
NO2
Pd/C, H2
Methanol
Piperidine, Cs2CO3
Toluene, reflux
for –NH proton and two multiplets at
d 6.90–7.05 and d
5B
7.20–7.49 for aniline and benzyl aromatic protons. The structure
of the compound 5B was confirmed by its 1H NMR spectrum which
showed characteristic peaks at d 3.09 (t) for 4 protons of two
methylene groups of piperidine ring adjacent to nitrogen and at d
1.64–1.76 (m) for 4 protons and at d 1.50–1.63 (m) for 2 protons
of piperidine ring.
Scheme 1.
R
R
OH
O
O
OBn
NO2
Pd/C, H2
CH3OH
At this juncture, with the compounds 5A and 5B in hand, we
wanted to get the desired reduction products 6A and 6B respec-
tively. When one pot catalytic hydrogenation reaction to de-pro-
tect benzyl group and simultaneous reduction of Nitro group
using 10% Pd on Carbon (wet) in Methanol was attempted under
the atmosphere of Hydrogen created with a balloon of Hydrogen
gas, a more polar spot on TLC was observed and surprisingly the
Rf value of the compounds obtained in both the reactions matched
exactly on TLC. The reaction mixture was then filtered and the sol-
vents were evaporated on rotary evaporator under reduced pres-
sure to obtain the crude products which were then purified by
column chromatography separately using silica gel (60–120 mesh
size) to get a red colored dye in overall 45% of yield (Scheme 2).
Analysis of both the compounds using 1H NMR showed identi-
cal pattern of peaks and confirmed the absence of peaks for aniline
and piperidine moieties. The spectrum showed peaks at d 6.48 (s)
for 1 proton, 6.42 (s) for 1 proton. At 6.76 a broad singlet was
observed for two protons which is a characteristic peak of –NH2
protons. The rest of the peaks were observed in aromatic region
at d 7.77 (d) for one proton, d 7.47–7.36 (m) for 3 protons. The mass
spectrum of both the compounds showed (M+1) peak at 213 con-
firming the mass of the Questiomycin A. The compound was fur-
ther confirmed by matching the analytical data of Questiomycin
A 1 with the reported compound.7
NH2
N
1
NH2
6
5
;
6A
= R =
6B
= R =
;
5A
5B
= R =
= R =
N
N
NH
NH
Scheme 2.
electroluminescent tools.24,25 These simple moieties have also
been used as building blocks in organic semiconductors.25
Regardless of the availability of derivatives and their synthetic
methods, there is a constant need to develop and explore synthetic
structures of phenoxazine moieties in order to get compounds
which are more efficient for DSSC. In this quest we are interested
in synthesizing derivatives with different amine functionalities
over the tricyclic core of the phenoxazine moieties.
We started the synthetic route from 2-nitrophenol 2. Bromina-
tion of the same with molecular bromine in 1:1 acetic acid and
water at room temperature yielded a sole bromophenol 3. The
structure of the compound was confirmed by 1H NMR, which
showed characteristic peaks at d 7.98 (d), d 7.67 (dd) and at d
7.08 (d). The phenolic group of the obtained compound 3 was pro-
tected with benzyl bromide in refluxing acetone in the presence of
potassium carbonate to yield compound 4. The compound 4 was
confirmed by its 1H NMR spectrum which showed characteristic
peaks at d 5.2 (s) for two benzylic protons and at d 7.3 to d 7.45
(m) for 5 protons. The obtained compound 4 was then reacted
Although the mechanism for deamination reaction is uncertain,
the probable mechanisms are depicted in Schemes 3–5. The elec-
tron density is high around C(aryl)–N bond, therefore it could
easily get adsorbed over the Pd metal surface, which could be
reduced with the adsorbed Hydrogen and cleave the C(aryl)–N
bond to yield the compound 5. Further, the benzylic deprotection
Tauto-
Michael
addition
OBn
NO2
OH
OH
O
N
-merism
+
O
OH
NH2
N
7
8
5
9
Michael
addition
O
OH
O
OH
NH
OH
N
O
OH
N
H
N
H
NH
N
H
12
11
H
10
Scheme 3.

6106
S. Mustafa et al. / Tetrahedron Letters 56 (2015) 6104–6107
OH
N
H
O
H
H
O-
O
N
O
N
+N
O
O
-H2O
Hydride
+
NH2
NH2
15
13
shift
OH
HN
H2N
HO
O
N
O
HN
H2O
+
NH2
O
HO
1
Scheme 5.
and the nitro group reduction of compound 5 could yield amino
compound 7 and nitroso compound 8. The first Michael reaction
of aminophenol 7 and the compound 9 which is a tautomer of 8
could furnish compound 10. The compound 11 which is a tautomer
of compound 10 could undergo an intramolecular Michael addition
reaction to yield iminophenol 12 (Scheme 3).
5.00; N, 8.71; O, 14.95. 1H NMR (CDCl3, 300 MHz): d 7.56(d, 1H,
J = 2.7 Hz), 7.36 (m, 7H), 7.19 (dd, 1H, J = 8.7, 2.7 Hz), 6.99 (m,
4H), 5.64 (s, 2H), 5.18 (s, 1H) ppm. 13C NMR (CDCl3, 75 MHz): d
146.38, 142.63, 140.89, 137.30, 136.06, 129.72, 128.79, 128.30,
127.26, 124.01, 121.87, 117.88, 117.37, 114.83, 72.18 ppm.
Being an oxidizing agent, the intermediate o-nitrosophenol 8 or
its quinoneimine form 9 could act like benzoquinone and react
Synthesis of 1-(2-(benzyloxy)-3-nitrophenyl) piperidine (5B)
with o-aminophenol derivative 13 which is
a tautomer of
Following the procedure mentioned above for the synthesis of
5A, piperidine (0.4 ml, 4.0 mmol) was added drop wise with the
syringe and the reaction mixture was stirred for 24 h at 90 °C. Then
the reaction mixture was filtered, diluted with ethyl acetate
(50 ml), and the organic layer was washed successively with water
(3 ꢀ 50 ml) and with brine solution. The organic layer was dried
over MgSO4, filtered, and the solvent was removed under reduced
pressure to get reddish brown precipitate which was purified by
column chromatography using EtOAc/Hexane (1:9 mixture) as an
eluent to afford red color dye (700 mg, 2.24 mmol). Mp 55–61 °C.
Anal. Calcd for C18H20N2O3 (312.36): C, 69.21; H, 6.45; N, 8.97; O,
15.37. Found: C, 69.18; H, 6.43; N, 8.94; O, 15.35. 1H NMR (CDCl3,
300 MHz): d 7.38 (m, 3H), 7.04 (m, 1H), 5.15 (s, 1H), 3.09 (t,
J = 5.4 Hz, 2H), 1.7 (m, 2H), 1.57 (m, 1H) ppm. 13C NMR (CDCl3,
o-iminophenol derivative 12 in the fashion shown in either
Scheme 4 or 5 to furnish the final compound Questiomycin A 1.
The mechanism is further supported by the catalytic hydrogena-
tion of o-nitrophenol using Pd/C in methanol under the atmo-
sphere of hydrogen, which afforded Questiomycin-A in overall
48% yield.
O
N
O
OH
Pd/C, H2
CH3OH
NH2
NO2
Conclusion
75 MHz):
d 145.08, 140.80, 136.33, 130.64, 128.92, 127.29,
In conclusion, an unexpected result was observed in the method
to cleave C(aryl)–N bond of 2-amino-6-nitrophenol derivatives
using easily available catalytic hydrogenation conditions. Very
few methods are available for the cleavage of C(aryl)–N bond.2,3
The deamination intermediates reacted further in the reaction con-
ditions to yield Questiomycin-A which is a novel synthetic reduc-
tive method for the synthesis of the pharmaceutically interesting
class of 2-aminophenoxazin-3-one. We believe the method dis-
closed is suitable for the synthesis of several related 2-aminophe-
noxazin-3-one derivatives.
127.11, 125.55, 122.78, 117.29, 72.25, 51.05, 25.79, 24.06 ppm.
Synthesis of 2-amino-3H-phenoxazin-3-one (1)
To the solution of Buchwald product 5 (200 mg) in methanol
(5 ml) was added wet 10% Pd/C (10 mg) and the reaction mixture
was stirred for 5 h under the pressure of hydrogen balloon. The
reaction mixture was then filtered, washed the solids with EtOAc
(2 ꢀ 10 ml), and the combined solvents were evaporated on a
rotary evaporator under reduced pressure to get the crude product
which was purified by column chromatography using EtOAc/
Hexane (1:4) to get a red colored dye (60 mg, 0.28 mmol in case
of 5A) and (56 mg, 0.26 mmol in case of 5B). Mp 147–152 °C (sub-
limation). Anal. Calcd for C12H8N2O2 (212.20): C, 67.92; H, 3.80; O,
15.08; N, 13.20. Found: C, 67.90; H, 3.78; O, 15.05; N, 13.17. 1H
NMR (CDCl3, 300 MHz): d 7.76 (d, 1H, J = 7.8 Hz), 7.41 (m, 3H),
6.73 (m, 2H), 6.48 (s, 1H), 6.42 (s, 1H).
Synthesis of 2-(benzyloxy)-3-nitro-N-phenylaniline (5A)
The benzylated compound 4 (1 g, 3.2 mmol), Pd2(dba)3 (20 mg,
0.021 mmol), 2-dicyclohexylphosphino-20,60-dimethoxybiphenyl
(20 mg, 0.048 mmol), cesium carbonate (1.96 g, 6.0 mmol) were
taken in a clean and dry sealed tube. Then toluene (20 ml) was
added with syringe. The reaction mixture was stirred under nitro-
gen at 90 °C. After 15 min aniline (0.4 ml, 8.6 mmol) was added
drop by drop with the help of syringe. The mixture was allowed
to stir for 24 h at 90 °C. Then the reaction mixture was filtered,
diluted with ethyl acetate (50 ml) and the organic layer was
washed successively with water (3 ꢀ 50 ml) and with brine solu-
tion. The organic layer was dried over MgSO4, filtered, and the sol-
vent was removed under reduced pressure to get reddish brown
precipitate which was purified by column chromatography using
EtOAc/Hexane (1:9 mixture) as an eluent to afford red color dye
(750 mg, 2.3 mmol). Mp 92–98 °C. Anal. Calcd for C19H16N2O3
(320.34): C, 71.24; H, 5.03; N, 8.74; O, 14.98. Found: C, 71.22; H,
Acknowledgements
Financial assistance from UGC – India with project F.No.
42-306/2013(SR) (New Delhi) is gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2015.09.
080.

S. Mustafa et al. / Tetrahedron Letters 56 (2015) 6104–6107
6107
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