A novel approach for C-C, C-N, and C-O Bond formation reactions: A facile synthesis of Benzophenazine, Quinoxaline, and Phenoxazine derivatives via Ring opening of Benzoxepines

Article abstract of DOI:10.1021/ol4033122

A new one-pot protocol has been developed for the synthesis of benzophenazine, quinoxaline, and phenoxazine derivatives by the reaction of benzoxepine-4-carboxylates with benzene-1,2-diamines, ethane-1,2-diamine, and 2-aminophenols in the presence of Bi(OTf)₃ (5 mol %) under mild conditions in very good yields. The present protocol opens a new way for C-C, C-N, and C-O bond-formation reactions in a single-step process. The structural assignment was confirmed by X-ray analysis.

Full text of DOI:10.1021/ol4033122

Letter
pubs.acs.org/OrgLett
A Novel Approach for C−C, C−N, and C−O Bond Formation
Reactions: A Facile Synthesis of Benzophenazine, Quinoxaline, and
Phenoxazine Derivatives via Ring Opening of Benzoxepines
Bhimapaka China Raju,*,† Kasagani Veera Prasad,† Gannerla Saidachary,† and Balasubramanian Sridhar‡
‡
†Natural Product Chemistry Division, Laboratory of X-ray Crystallography, CSIR-Indian Institute of Chemical Technology, Uppal
Road, Tarnaka, Hyderabad, 500 007, India
S
* Supporting Information
ABSTRACT: A new one-pot protocol has been developed for the synthesis of benzophenazine, quinoxaline, and phenoxazine
derivatives by the reaction of benzoxepine-4-carboxylates with benzene-1,2-diamines, ethane-1,2-diamine, and 2-aminophenols in
the presence of Bi(OTf)3 (5 mol %) under mild conditions in very good yields. The present protocol opens a new way for C−C,
C−N, and C−O bond-formation reactions in a single-step process. The structural assignment was confirmed by X-ray analysis.
henazines, quinoxalines, and phenoxazines are important
diamines with epoxides or dicarbonyl compounds or their
Pheterocyclic compounds in the pharmaceutical industry. equivalents.12 The approaches for the synthesis of phenoxazines
1
consist of the following: (1) Smiles rearrangements13a−d of 2′-
Phenazines and their derivatives have found application in a
aminodiaryl ethers; (2) reaction between 2-aminophenols and
chalcones;13e (3) Cu-catalyzed preparation of substituted
phenoxazine derivatives;7 and (4) base catalyzed cyclization
of N-acetyl aryloxyanilides.13f However, the development of
simple and novel methodologies for these heterocycles is still
required.
wide variety of therapeutics, which include antibiotic,
antimicrobial, antimalarial, antiparasitic, and antitumor activ-
ities.2 The phenazine derivatives were also reported as
photosensitizers in photodynamic therapy (PDT).3 Quinoxa-
lines4 are benzoheterocycles possessing various pharmacolog-
ical activities including anticancer, antimicrobial, and building
blocks of organic semiconductors. Phenoxazine is an important
pharmacophore present in Actinomycin D, a chemotherapy
drug,5 and several phenoxazines have been reported as
anticancer agents,6,1c MDR modulators,7 and potent specific
inhibitors of Akt signaling.8 Further, N-benzoylated phenox-
azines have been reported as tubulin polymerization inhibitors.9
The phenoxazines and benzophenoxazines were also reported
as fluorescent dyes.10 Therefore, the development of novel
synthetic methods for these heterocycles continues to be an
active area of research. Few synthetic approaches have been
reported as depicted below.
The approaches for the synthesis of phenazines consist of
(Scheme 1): (a) base catalyzed condensation of anilines with
nitrobenzenes at 200 °C11a (Wohl−Aue method); (b) fusing of
two molecules of 4-substituted nitrosobenzene under acidic
conditions11b (Bamberger−Ham method); (c) dehydrative
condensation of benzo[1,2,5]oxadiazole-1-oxide with nucleo-
philes11c (Beirut reaction); (d) condensation of catechols with
benzene-1,2-diamine11d or in presence of PbO2; and (e)
sequential palladium(II) catalyzed aryl amination (Buchwald−
Hartwig).11e−h Methods a−d received limited attention due to
the harsh reaction conditions with poor yields.11a−d Quinoxa-
lines are usually synthesized by condensation of aryl-1,2-
Our research focused on the synthesis of biologically active
heterocyclic compounds,14 and feasible reactions of carbonyl
compounds/salicylaldehydes with 3-oxobutanoates bearing
chloro or trifluoro substituents. In this context, we studied
the reactivity of carbonyl compounds with ethyl 4,4,4-trifluoro-
3-oxobutanoate using piperidine in CH2Cl2 at room temper-
ature to provide a series of (E)-α,β-unsaturated esters and
ketones.15 Next, we studied the reactivity of various
salicylaldehydes with ethyl 4-chloro-3-oxobutanoate using
piperidine to provide 2H-chromenes,16a interim these deriva-
tives were successfully converted to corresponding 2,3-dihydro-
benzoxepine-4-carboxylates.16b Now, the present manuscript
describes a novel method for the preparation of benzophena-
zine, quinoxaline, and phenoxazine derivatives in one pot from
benzoxepine-4-carboxylates.
In an initial experiment, we conducted the reaction between
the benzoxepine-4-carboxylate (1a, 1 equiv) and benzene-1,2-
diamine (2a, 1 equiv) at 110 °C. This afforded ethyl
benzo[a]phenazine-6-carboxylate 3a in 30% isolated yield
(Table 1, entry 1). The phenazine derivative 3a was fully
Received: November 16, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
the first example of the construction of benzophenazine in one
pot, and the usefulness of this reaction is shown by the
formation of three new bonds (one C−C bond, two C−N
bonds) and two new rings (naphthalene and quinoxaline). To
optimize the reaction conditions, the model reaction was
investigated with various catalysts and solvents, and the results
were summarized in Table 1. The product 3a was obtained in
32% (18 h), 44% yield (36 h) when the reaction was carried out
at room temperature with Bi(OTf)3 (5 mol %).17 Toluene
provided a higher yield (3a, 84%) when 1a was reacted with 2a
in the presence of Bi(OTf)3 (5 mol %) under reflux conditions
than did other organic solvents (entries 4−8); hence, toluene
was chosen as the solvent for further reactions. Compound 3a
was obtained in 65% yield when the reaction was carried out
with La(OTf)3 (entry 10). The catalysts such as protic acids
(entries 11−16), Lewis acids (entries 17−20), an ionic liquid
(entry 21), and p-TsOH (entry 22) were screened. In all the
reactions, product 3a was obtained but in less yields except in
the case of acetic acid (72%, entry 14). These experiments
showed that the reaction of a 1:1:0.05 mixture of benzoxepine
(1a), benzene-1,2-diamine (2a), and Bi(OTf)3 in toluene under
reflux conditions (4 h) provided 3a in a higher yield.
Scheme 1. Approaches for the Synthesis of Phenazines
In order to evaluate the efficiency of the methodology, we
investigated the substrate scope present on benzoxepine-4-
carboxylates (1b−l) and benzene-1,2-diamine (2b−e). The
electron-withdrawing or -donating groups present on benzox-
epine were well tolerated to produce 3b−h in very good yields,
whereas groups present on benzene-1,2-diamine produced 3i−l
in moderate yields (Scheme 2). Thus prepared benzo-
phenazine-6-carboxylate derivatives 3a−l were well character-
Table 1. Optimization of the Reaction Conditions
1
ized using IR, H NMR, 13C NMR, and MS spectroscopies.
Scheme 2. Synthesis of Benzophenazine-6-carboxylate
a
−c
Derivatives 3a−l
d
entry
catalyst (equiv)
solvent
time (h)
yield (%)
a
1
−
−
48
18
36
04
12
12
12
12
24
08
24
16
20
05
20
20
16
20
20
16
24
16
30
32
44
84
58
60
52
−
18
65
10
28
34
72
42
48
63
28
59
12
12
64
b
2
Bi(OTf)3 (0.05)
Bi(OTf)3 (0.10)
Bi(OTf)3 (0.05)
Bi(OTf)3 (0.05)
Bi(OTf)3 (0.05)
Bi(OTf)3 (0.05)
Bi(OTf)3 (0.05)
La(OTf)3 (0.05)
La(OTf)3 (0.05)
AcOH
toluene
toluene
toluene
MeOH
DCM
b
3
c
4
c
5
c
6
c
7
CH3CN
THF
c
8
b
9
toluene
toluene
−
c
10
b
11
c
12
AcOH
−
b
13
AcOH (1.5)
AcOH (1.5)
H2SO4 (1.0)
HCl (1.0)
toluene
toluene
toluene
toluene
CH3CN
toluene
toluene
toluene
−
c
14
c
15
c
16
a
c
Reaction conditions: 1 (1 mmol), 2 (1 mmol), Bi(OTf)3 (5 mol %)
or AcOH (1.5 equiv), and toluene (4.0 mL) in a round-bottom flask
17
AlCl3 (1.0)
c
18
AlCl3 (1.0)
b
c
under reflux.
Isolated yield. Regioisomers were obtained for
c
19
FeCl3 (1.0)
compounds 3j (95:5), 3k (98:2), and 3l (60:40).
c
20
I2 (1.0)
c
21
BMIM-Cl
c
22
p-TsOH (1.0)
toluene
To expand the scope of the present method, ethane-1,2-
diamine (2aa) and propane-1,3-diamine (2ab) were examined.
Under optimized conditions, 1a was reacted with ethane-1,2-
diamine 2aa producing benzoquinoxaline-5-carboxylate 4a in
58% yield (Scheme 3). Phenyl and methoxy groups present on
benzoxepine were well tolerated to produce 4b−c. Under these
a
b
c
d
110 °C. Room temperature. Reflux. Isolated yields.
characterized using IR, 1H NMR, 13C NMR, and HRMS
spectroscopies. The structure of 3a was further confirmed using
single-crystal X-ray diffraction analysis. This work represents
B
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Letter
Scheme 3. Synthesis of Benzoquinoxaline-5-carboxylate
Derivatives 4a−c
Scheme 5. Synthesis of Benzophenoxazine-6-carboxylate
a
a
,b
,b
Derivatives 6a−e
a
Reaction conditions: 1 (1 mmol), 2 (1 mmol), and Bi(OTf)3 (5 mol
b
%) or AcOH (1.5 equiv) in toluene (4.0 mL) under reflux. Isolated
yield.
a
conditions, propane-1,3-diamine 2ab and 2-amino ethanol 2ac
did not yield the desired products.
A proposed mechanism for this new reaction is shown in
Scheme 4. Initially, the reaction was expected to involve
Reaction conditions: 1 (1.0 mmol), 2 (1.0 mmol), and Bi(OTf)3 (5
mol %) or AcOH (1.5 equiv) in toluene (4.0 mL) under reflux.
Isolated yield.
b
one pot by C−C, C−N, and C−O bond-forming reactions.
Due to the importance of these heterocyclic compounds
especially in pharmaceutical and medicinal chemistry, the
present protocol can be further extended for the synthesis of
various biologically important heterocyclic compounds.
Scheme 4. Proposed Mechanism for Phenazines
ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental details, characterization data of the products,
1
copies of H and 13C NMR spectras and X-ray crystallography
data. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
enolization of benzoxepine 1a to its corresponding enol
derivative A. Protonation of intermediate A would then give
oxonium ion B. Finally the unstable oxonium ion B was
rearranged by C−O bond cleavage to form a new C−C bond to
give its corresponding ethyl 3,4-dihydroxy-2-naphthoate C (1H
NMR experiment; see Supporting Information (SI); the
naphthoate was isolated and confirmed by D2O exchange).
Condensation of ethyl 3,4-dihydroxy-2-naphthoate C with
benzene-1,2-diamine in situ provided phenazine derivative 3a.
Having succeeded in the synthesis of benzophenazines and
quinoxalines, we extended this protocol for the preparation of
benzophenoxazines. Accordingly, benzoxepines 1a, 1d−e were
reacted with various substituted 2-aminophenols 5a−e in the
presence of Bi(OTf)3 under optimized conditions to provide a
series of benzophenoxazine-6-carboxylates 6a−e in very good
yields (Scheme 5). The formation of benzophenoxazine 6a is
regioselective due to the hydrogen bonding (carboxylate
function with the adjacent amine, SI). Under these conditions,
the use of 2-aminothiophenol is futile. The phenoxazine
*E-mail: chinaraju@iict.res.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
K.V.P. thanks UGC and G.S. thanks CSIR, New Delhi for
fellowships. B.C.R. acknowledges CSIR, New Delhi for financial
support through the programme ORIGIN (CSC0108) of XII
five year plan.
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