Synthesis of phenazines from ortho-bromo azo compounds via sequential Buchwald-Hartwig amination under micellar conditions and acid promoted cyclization

Article abstract of DOI:10.1016/j.tetlet.2020.152511

Non-symmetric phenazines were synthesized via the Buchwald-Hartwig amination of ortho-bromoazobenzenes with anilines under micellar conditions, using the commercially available surfactant Kolliphor EL in water, followed by an acid-promoted 6π-electrocyclization-aromatization process. Two different synthetic pathways to obtain the ortho-bromo azo intermediates were explored, namely the palladium catalysed selective ortho bromination of azobenzenes and the diazo coupling of ortho-bromo diazonium salts with N,N-dimethylaniline, imidazole, phenol, sodium methanesulfinate and ethyl chloroformate.

Full text of DOI:10.1016/j.tetlet.2020.152511

Tetrahedron Letters 61 (2020) 152511
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Synthesis of phenazines from ortho-bromo azo compounds via
sequential Buchwald-Hartwig amination under micellar conditions
and acid promoted cyclization
⇑
Dawod Yousif, Mauro Monti, Antonio Papagni, Luca Vaghi
Department of Materials Science, University of Milano-Bicocca, Via Cozzi 55, 20125 Milano, Italy
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 30 July 2020
Revised 24 September 2020
Accepted 28 September 2020
Available online 7 October 2020
Non-symmetric phenazines were synthesized via the Buchwald-Hartwig amination of ortho-bromoa-
zobenzenes with anilines under micellar conditions, using the commercially available surfactant
Kolliphor EL in water, followed by an acid-promoted 6p-electrocyclization-aromatization process. Two
different synthetic pathways to obtain the ortho-bromo azo intermediates were explored, namely the pal-
ladium catalysed selective ortho bromination of azobenzenes and the diazo coupling of ortho-bromo dia-
zonium salts with N,N-dimethylaniline, imidazole, phenol, sodium methanesulfinate and ethyl
chloroformate.
Keywords:
Phenazines
Azobenzenes
Ó 2020 Elsevier Ltd. All rights reserved.
Micellar synthesis
Buchwald-Hartwig amination
Electrocyclization
Introduction
sive reagents and catalysts, especially in the case of non-symmetric
phenazines.
Phenazines are tricyclic heteroaromatic systems characterized
by a central pyrazine ring fused with two benzenes on its sides.
Their discovery dates to the middle of the 19th century, when pyo-
cyanin, a blue pigment, was extracted from the wounds of patients
infected by the gram-negative bacterium P. aeruginosa [1,2]. Since
then, hundreds of phenazine based compounds have been isolated
from natural sources and have displayed interesting biological
properties [3,4]. For example, those isolated from Pseudomonas
and Streptomyces organisms possess important biological proper-
ties such as chemopreventivity against cancer, antifungal activity
and the ability to eradicate biofilm in the treatment of antibiotic
resistant bacteria [5–8]. Furthermore, the peculiar optical and
redox properties of the phenazinic system have recently been
exploited in notable applications, such as the synthesis of electro-
luminescent copolymers for LED fabrication, solution-processed
organic bulk-heterojunction solar cells and the photochemical oxi-
dation of water [9–11]. Notwithstanding these interesting proper-
ties and applications, to date there has been limited accessibility to
phenazines from commercial sources, and this could be ascribed to
the shortage of efficient and convenient synthetic methods that
avoid harsh experimental conditions as well as the use of expen-
In this context, we recently developed new methodology for the
synthesis of non-symmetric polyfluorinated phenazines, based on
the sequential selective ortho nucleophilic aromatic substitution
of polyfluoro azobenzenes with anilines, followed by an acid-catal-
ysed 6p-electrocyclization-aromatization process [12]. However,
the applicability of this protocol is limited to highly fluorinated
azobenzenes and the main drawbacks of the strategy are the inevi-
table low yields in the oxidation of polyfluoroanilines to polyfluo-
roazobenzenes [13], and the loss of 50% of the starting aniline
during the final cyclization step, since only one aromatic ring of
the azo derivative is incorporated in the final phenazine unit. With
the aim of expanding the scope of this synthetic method, we
focused on our recently developed process to afford non-symmet-
ric acridines [14], which is, in some key steps, very similar to that
developed for polyfluorophenazines [12]. Indeed, the acridine sys-
tem is produced by an acid catalysed cyclization of ortho-anili-
nated benzaldehydes, which can be synthesised by an effective
Buchwald-Hartwig (B-H) amination conducted under micellar con-
ditions in water on the corresponding ortho-bromobenzaldehydes.
The field of micellar synthetic chemistry has seen significant inter-
est in recent years, switching the use of surfactants from dispersing
lipophilic substances in water to the creation of nanoreactors in
aqueous environments, affording chemical transformations in a
more efficient and environmentally compliant way [15,16]. For
⇑
Corresponding author.
E-mail address: luca.vaghi@unimib.it (L. Vaghi).
https://doi.org/10.1016/j.tetlet.2020.152511
0040-4039/Ó 2020 Elsevier Ltd. All rights reserved.

D. Yousif, M. Monti, A. Papagni et al.
Tetrahedron Letters 61 (2020) 152511
Table 1
our purposes we used the commercially available surfactant Kol-
liphor EL (2% w/w in water), giving better results than those
obtained in an organic solvent [14]. Moreover, there was no need
for an inert atmosphere, as the use of this surfactant demonstrated
unprecedented resistance to oxygen permeability of the reaction
environment [17]. In order to apply the micellar methodology to
the synthesis of phenazines, we planned to substitute the nucle-
ophilic aromatic substitution with a micellar type B-H amination,
therefore using ortho-bromo azobenzenes as key intermediates
instead of highly fluorinated azo compounds, resulting in a more
general protocol allowing the production of a wide range of non–
symmetric phenazines.
Optimization of the micellar B-H between 3 and 1.
N
NH2
N
N
N
NH
+
Br
1
3
7
Entry
Temperature
Reaction time
Yield 7 (%)a
1
2
3
4
5
6
60 °C
60 °C
80 °C
80 °C
80 °C
80 °C
2 h
20 h
2 h
4 h
20 h
48 h
–
trace
10
23
91
89
Results and discussion
In an initial effort to prove our synthetic strategy we first pre-
pared 1-(2-bromophenyl)-2-phenyldiazene 3 (Scheme 1), starting
from the oxidation of aniline 1 with CuBr/pyridine under air to give
azobenzene 2 in 77% yield [18], and subsequent selective palla-
dium catalysed mono ortho bromination by the method of Tian
and co-workers [19].
Reagents and conditions: 3 (0.5 mmol), 1 (0.5 mmol), Pd2(dba)3 (2 mol%), dppf
(4 mol%), t-BuONa (0.75 mmol), Kolliphor EL (1.97% H2O, 1.8 mL), toluene (0.2 mL),
stirring (500 rpm). aIsolated yield.
Initially, we examined the B-H reaction under micellar condi-
tions between 3 and aniline 1 (Table 1). As a starting point we
selected the previously reported conditions used for the amination
of ortho-bromo benzaldehydes [14], i.e. 3 and 1 in a 1:1 ratio, Pd2(-
dba)3 as precatalyst, dppf as ligand, sodium tert-butoxide as base in
a mixture of 1.97% aqueous Kolliphor EL and toluene in a 9:1 ratio,
at 60 °C, with 500 rpm stirring, under air (Table 1, entry 1). Under
these conditions no traces of the desired product 7 (Scheme 2)
were detected, and the starting reactants 1 and 3 remained unal-
tered. Upon increasing the reaction time from 2 h to 20 h (Table 1,
entry 2), barely detectable traces of the product were found. We
hypothesized that the activation energy for this transformation
could be higher with respect to the B-H on ortho-bromo benzalde-
hydes, thus we considered further increasing the reaction temper-
ature. Running the reaction at 80 °C for 2 h (Table 1, entry 3) was
beneficial and afforded 7 in 10% isolated yield. At this point we
decided not to further raise the temperature to avoid exceeding
the cloud point, and therefore the phase separation of the micellar
reaction media. Maintaining the temperature at 80 °C the reaction
was run for 4 h (Table 1, entry 4), and the yield increased to 23%.
Finally, with a reaction time of 20 h under these conditions, we
were able to obtain 7 in 91% isolated yield (Table 1, entry 5). The
use of a longer reaction time was unfruitful (Table 1, entry 6).
With these optimized conditions for the micellar B-H amina-
tion of 3, we synthesized ortho aminated azo compounds 8, 9
and 10, using 2-methoxyaniline 4, 2,4,5-trifluoroaniline 5 and 2-
aminophenol 6, respectively (Scheme 2). Our choice to use ortho
oxygenated anilines was driven by their interesting biological
activity against resistant bacteria demonstrated by phenazines
possessing the hydroxy functionality in position 1 [5,7,8]. More-
over, 4 and 5 were selected as electron-rich and an electron-poor
aminating agents. Due to steric hindrance, a decreased yield was
observed with both 4 and 5, which was more pronounced using
NH2
N
N
1
NH2
4
NH
(91%)
7
OMe
N
N
NH
OMe
NH2
(85%)
8
F
a
N
N
F
N
Br
N
F
5
3
NH
F
F
F
9
NH2
(71%)
OH
N
N
6
NH
NH2
OH
a
b
N
N
N
N
Br
(70%)
10
1
(77%)
(94%)
3
2
Scheme 2. Micellar B-H amination of 3 with anilines. Reagents and conditions: (a)
3 (0.5 mmol), aniline (0.5 mmol), Pd2(dba)3 (2 mol%), dppf (4 mol%), t-BuONa
(0.75 mmol), Kolliphor EL (1.97% H2O, 1.8 mL), toluene (0.2 mL), 80 °C, 20 h, stirring
(500 rpm).
Scheme 1. Preparation of 1-(2-bromophenyl)-2-phenyldiazene 3. Reagents and
conditions: (a) CuBr (6 mol%), pyridine (18 mol%), toluene, 60 °C, air (1 atm.), 20 h;
(b) NBS (1.2 equiv.), Pd(OAc)2 (5 mol%), TsOH (0.5 equiv.), CH3CN, r.t., 20 h.
2

D. Yousif, M. Monti, A. Papagni et al.
Tetrahedron Letters 61 (2020) 152511
NMe2
NH2
NMe2
N
N
a, b
Br
Br
Br
N
N
+
N
a
a
NH
Br
21
N
15
16
(80%)
O
(95%)
11
NH2
Me
O
S
N
S
c, d
N
7
+
+
O
Me
Cl
ONa
Br
N
N
N
N
15
17
(50%)
22
NH
O
NH2
O
a, e, f, g
OMe
N
OMe
N
OEt
OEt
(96%)
12
Br
8
15
18
(46%)
23
N
NH2
N
N
N
F
F
N
N
Br
Br
a, h
a, i
N
H
N
F
N
H
+
+
a
a
NH
F
Br
N
15
19
(38%)
24
OH
13
F
F
9
NH2
OH
N
N
Br
25
N
N
15
20
(22%)
N
N
Scheme 5. Synthesis of ortho-bromoaryl azo derivatives. Reagents and conditions:
(a) 15 (0.5 g, 3 mmol), NaNO2 (225 mg, 3.3 mmol), HClaq (12 N, 2 mL), H2O (6 mL),
0 °C, 20 min; (b) 16 (363 mg, 3 mmol), AcOH (0.5 mL), 0 °C to r.t., 20 h; (c) 15 (1.7 g,
9.9 mmol), NaNO2 (0.68 g, 9.9 mmol), HBF4 (48% wt. in H2O, 3.4 mL), H2O (5 mL),
0 °C, 20 min; (d) 17 (1 g, 9.9 mmol), Na2SO4 (5 g, 35 mmol), acetone (30 mL), r.t.,
20 h; (e) SnCl2 (1.6 g, 6.9 mmol), HClaq (12 N, 1 mL), 0 °C, 10 min; (f) 18 (423 mg,
3.9 mmol), pyridine (300 mg, 3.8 mmol), acetonitrile (7 mL), r,t., 10 min; (g) PhI
(OAc)2 (450 mg, 1.4 mmol), CH2Cl2 (5 mL), r.t., 1 h; (h) 19 (205 mg, 3 mmol), Na2CO3
(3 g, 28 mmol), H2O (20 mL), 0 °C to r.t., 20 h; (i) 20 (282 mg, 3 mmol), KOH (3 g,
53 mmol), H2O (20 mL), 0 °C to r.t., 20 h.
NH
OH
OH
(37%)
14
10
Scheme 3. Acid catalysed 6p-electrocyclization-aromatization process to phena-
zines. Reagents and conditions: (a) TFA (5 mL), room temperature, overnight.
obtained with compounds 7 and 8, affording phenazines 11 and
12 in 95% and 96% isolated yields, respectively. The treatment of
9 with TFA resulted in a mixture of unidentified products, with
no traces of phenazine 13. The trifluorophenyl ring is presumably
N
N
N
N
a
b
NH
3
too electron-deficient to enable the 6p-electrocyclization process,
X
X
making the use of strong electron-poor anilines unsuitable for this
strategy. As confirmation we also treated compound 9 with con-
centrated H2SO4 with identical results.
(90%)
(82%)
(27%)
11
12
14
The next step was to investigate the feasibility of a sequential
procedure without isolation of the ortho aminated azo intermedi-
ate. Thus, the work-up of the reaction mixture arising from the
micellar B-H concerned the removal of all volatiles followed by
rapid passage through a short pad of silica gel. The crude filtrate
was then treated with TFA to promote the cyclization reaction.
With this procedure we were able to directly synthesize phenazi-
nes 11, 12 and 14 from ortho-bromo azobenzene 3 in 90%, 82%
and 27% yield, respectively (Scheme 4).
With this method we were able to obtain phenazines from
azobenzene 2 in up to 85% overall yield, over two synthetic steps,
i.e. regioselective ortho bromination and sequential B-H/cycliza-
tion. However, the method of Tian and co-workers cannot be used
to brominate the more electron-poor ring of non-symmetric
azobenzenes; the bromination will inevitably proceed on the more
electron-rich ring. Moreover, the bromination is less effective using
some substituted azobenzenes [19]. With these concerns in mind,
Scheme 4. Sequential B-H/cyclization from 3. Reagents and conditions: (a)
3
(0.5 mmol), aniline (0.5 mmol), Pd2(dba)3 (2 mol%), dppf (4 mol%), t-BuONa
(0.75 mmol), Kolliphor EL (1.97% H2O, 1.8 mL), toluene (0.2 mL), 80 °C, 20 h, stirring
(500 rpm); (b) TFA (5 mL), room temperature, overnight.
the electron-poor aniline 5. 2-Aminophenol 6 was used to deter-
mine if the presence of a phenolic hydroxy group on the aniline
could be tolerated in this transformation. Compound 10 was
achieved in a satisfactory 70% isolated yield, confirming the
compatibility of OH groups on anilines in the micellar B-H
reaction.
The ortho-anilino azo products 7, 8, 9 and 10 were then stirred
at room temperature overnight in trifluoroacetic acid (TFA), in
order to promote the acid-catalysed 6
p-electrocyclic reaction to
the desired phenazines (Scheme 3) [12]. Excellent results were
3

D. Yousif, M. Monti, A. Papagni et al.
Tetrahedron Letters 61 (2020) 152511
Table 2
Sequential B-H/cyclization of ortho-bromoaryl azo derivatives.
Y
Y
N
N
N
N
N
or , a
b
1
4
N
X
N
H
Br
X
Entry
Azo compound
Aniline
Phenazine
Yield (%)a
1
2
3
4
5
6
7
8
9
10
21
21
22
22
23
23
24
24
25
25
1
4
1
4
1
4
1
4
1
4
11
12
11
12
11
12
11
12
11
12
89
76
–
–
–
–
–
–
–
–
Reagents and conditions: azo compound (a) (0.5 mmol); aniline (0.5 mmol), Pd2(dba)3 (2 mol%), dppf (4 mol%), t-BuONa (0.75 mmol), Kolliphor EL (1.97% H2O, 1.8 mL),
toluene (0.2 mL), 80 °C, 20 h, stirring (500 rpm), (b) TFA (5 mL), room temperature, overnight. aIsolated yield over two steps.
The prepared ortho-bromoaryl azo substrates 21–25 were then
subjected to the sequential B-H/cyclization protocol with anilines 1
and 4 (Table 2).
NH2
NMe2
NMe2
Br
F
F
N
a, b
N
+
Only the N,N-dimethylamino derivative 21 gave satisfactory
results in the tandem B-H/cyclization procedure, affording
phenazines 11 and 12 in 89% and 76% yield, respectively (Table 2,
entries 1 and 2). No traces of the target phenazines were detected
in the cases of other ortho-bromoaryl azo starting materials
(Table 2, entries 3–10). To investigate if these failures were caused
by the inefficiency of the B-H or the TFA catalysed cyclization, we
re-ran the reactions with the objective of isolating the ortho-ani-
lino intermediates after the B-H step. Surprisingly, we were not
able to isolate the expected ortho-anilino azo derivatives from
the B-H reaction using compounds 22, 23, 24 and 25, thus ascribing
this failure to the amination step. In the cases of compounds 22
and 23 we hypothesized the cause to lie in the instability of the
nitrogen-sulphur and nitrogen-carbonyl bonds to the palladium
catalysis, while for compounds 24 and 25 an incompatibility with
the micellar B-H protocol was caused by the deprotonation of imi-
dazole and phenol, respectively.
F
Br
F
26
16
(70%)
27
F
N
1
c
27
27
F
N
(78%)
28
F
F
N
N
4
c
OMe
(76%)
29
Scheme 6. Synthesis of phenazines 28 and 29 via the diazo coupling and B-
H/cyclization of 2-bromo-4,5-difluoroaniline 26. Reagents and conditions: (a) 26
(625 mg, 3 mmol), NaNO2 (225 mg, 3.3 mmol), HClaq (12 N, 2 mL), H2O (6 mL), 0 °C
20 min; (b) 16 (363 mg, 3 mmol), AcOH (0.5 mL), 0 °C to r.t., 20 h; (c) Pd2(dba)3
(2 mol%), dppf (4 mol%), t-BuONa (1.5 equiv.), Kolliphor EL (1.97% H2O, 1.8 mL),
toluene (0.2 mL), 80 °C, 20 h, stirring (500 rpm); then TFA (5 mL), room
temperature, overnight.
To prove the efficacy of the method we selected a different
starting ortho-bromo aniline, i.e. 2-bromo-4,5-difluoroaniline 26
(Scheme 6). The diazo coupling with N,N-dimethylaniline 16 gave
ortho-bromo azobenzene 27 in 70% yield, and tandem B-H/cycliza-
tion the allowed us to obtain the target difluoro phenazines 28 and
29 in 78% and 76% yield, respectively.
Conclusion
we searched for an alternative method to obtain the ortho-bromo
azo intermediates in a more general way. Hundreds of substituted
ortho-bromo anilines are commercially available, and the synthesis
of target azo compounds via the azo coupling reaction seemed an
interesting option [20]. Furthermore, considering that only the aro-
matic ring bearing the bromine atom contributes to the final phe-
nazine unit allows the possibility to use asymmetric azo
derivatives with a less expensive part than that which is incorpo-
rated. In order to evaluate suitable starting materials for this
approach, a series of ortho-bromoaryl azo derivatives were synthe-
sized starting from 2-bromoaniline 15 via reported diazo coupling
protocols (Scheme 5) [21–25]. The yields ranged from 22% for com-
pound 25 to 80% in the case of the N,N-dimethylanilino derivative
21. The synthesis of compounds 24 and 25 was not straightforward
due to the formation of unwanted poly-diazo coupling products
[26,27].
In summary, we have described a new procedure for the syn-
thesis of non-symmetric phenazines from ortho-bromo azo com-
pounds via sequential micellar Buchwald-Hartwig amination and
acid promoted 6p-electrocyclization-aromatization process. The
objective was achieved through two different synthetic pathways
to give ortho-bromo azo intermediates; the palladium catalysed
selective ortho bromination of azobenzenes and the use of ortho-
bromo anilines for the diazo coupling of N,N-dimethylaniline. We
have demonstrated that the B-H amination step can be efficiently
carried out under micellar conditions in water and without the
need of an inert atmosphere using the inexpensive and commer-
cially available surfactant Kolliphor EL. Moreover, the final cycliza-
tion to phenazines can be easily performed by treating the crude
product from the amination step with TFA that acts both as a cat-
alyst and solvent.
4

D. Yousif, M. Monti, A. Papagni et al.
Tetrahedron Letters 61 (2020) 152511
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Declaration of Competing Interest
The authors declare that they have no known competing finan-
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Appendix A. Supplementary data
Experimental details; 1H, 19F, 13C NMR and ATR FT-IR spectra of
novel compounds. Supplementary data to this article can be found
online at https://doi.org/10.1016/j.tetlet.2020.152511.
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