Reactivity and substituent effects in the cyclization of N-aryl-2-nitrosoanilines to phenazines

Article abstract of DOI:10.1016/j.tet.2017.04.046

Reactivity of variously substituted N-aryl-2-nitrosoanilines in the reaction of cyclization leading to phenazine derivatives, carried out in the presence of N,O-bis(trimethylsilyl)acetamide (BSA), was estimated on the base of the observed reaction times. A strong opposite effect of substituents located at position para to the nitroso group and those located para to the amino group in the side ring was observed. Mechanistic explanation, based on the electronic properties of the substituents and their mesomeric effects, was presented. The usefulness of the obtained data for the designed syntheses of phenazines was exposed.

Full text of DOI:10.1016/j.tet.2017.04.046

Accepted Manuscript
Reactivity and substituent effects in the cyclization of N-aryl-2-nitrosoanilines to
phenazines
Zbigniew Wróbel, Karolina Plichta, Andrzej Kwast
PII:
S0040-4020(17)30436-2
10.1016/j.tet.2017.04.046
TET 28647
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 28 December 2016
Revised Date: 3 April 2017
Accepted Date: 20 April 2017
Please cite this article as: Wróbel Z, Plichta K, Kwast A, Reactivity and substituent effects in the
cyclization of N-aryl-2-nitrosoanilines to phenazines, Tetrahedron (2017), doi: 10.1016/j.tet.2017.04.046.
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ACCEPTED MANUSCRIPT
Graphical Abstract
O
N
O
N
Me3Si
H
Y
N
Y
BSA/DMF
r.t.
X
N
H
X
N
X
N
H
+
reaction time
0.5 - 480 h
77 - 92% yield
Rate determining addition
Oposite substituents effect
Y
X = EWG or Y = EDG
X = EDG or Y = EWG
high reactivity
low reactivity
X, Y = NMe2, OMe, H, Cl, F, CF3, CN
1

ACCEPTED MANUSCRIPT
Reactivity and substituent effects in the cyclization of N-aryl-2-
nitrosoanilines to phenazines.
Zbigniew Wróbel,* Karolina Plichta, Andrzej Kwast.
Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44, 01-224
Warsaw, Poland.
Keywords: cyclization, nitroso group, heterocyclic compounds
Abstract:
Reactivity of variously substituted N-aryl-2-nitrosoanilines in the reaction of
cyclization leading to phenazine derivatives, carried out in the presence of N,O-
bis(trimethylsilyl)acetamide (BSA), was estimated on the base of the observed reaction times.
A strong opposite effect of substituents located at position para to the nitroso group and those
located para to the amino group in the side ring was observed. Mechanistic explanation,
based on the electronic properties of the substituents and their mesomeric effects, was
presented. The usefulness of the obtained data for the designed syntheses of phenazines was
exposed.
1. Introduction
Phenazine, its substituted derivatives as well as various aza analogues have been isolated from
natural materials and synthesized for more than one hundred years. Nevertheless, due to their
important occurrence as a core in both natural and synthetic compounds of valuable biological
activity, interest in developing new methods for the synthesis of phenazine derivatives seems
not to be falling.1 Numerous methods for the synthesis of substituted phenazines have been
reported, however, they have several limitations, thus can not be considered as being
generally applicable.1, 2 This is because most of them are restricted to a narrow collection of
substituents and/or a specific substitution pattern of the target phenazine system. Two general
strategies, with their numerous variants, are now commonly employed. One of them is based
on the condensation of ortho-arylenediamines3 or benzofuroxans4 with the other suitably
functionalized aromatic reagent. The second one, which is more popular, relies on
* Corresponding author. e-mail address: zbigniew.wrobel@icho.edu.pl (Z. Wróbel).
2

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intramolecular cyclization of diarylamine derivatives, ortho-substituted with appropriate
nitrogen functions. such as NH2 or NO2. The cyclization process can occur, depending on the
oxidation state of that group, as oxidative5 or reductive1e,6 process. The starting diarylamines
are usually obtained from appropriate ortho-halogenonitroarenes, which is often not an easy
task. In some older methods either they, or their oxidized forms, can be considered as unstable
intermediates. This is the case of the Wohl-Aue reaction,7 where under strong basic conditions
nitrobenzene condenses with aniline to form phenazine, and the accepted mechanism of which
assumes formation of 2-nitrosodiphenylamine as direct intermediate in the cyclization.7b The
reaction could be attractive as it consists of only one step, and involves easy procedure
starting from simple and available substrates. However, reaction conditions are harsh and
strongly basic, the yields are low to moderate and the desired products are accompanied with
N-oxides and significant amounts of by-products.8 Therefore, the reaction has never found
extensive application. The situation has changed entirely after it was revealed that this two-
step reaction can be divided into two separate steps, both carried out under optimized
conditions. In 2008 we demonstrated that when the anilide anion generated by t-BuOK in
THF or DMF at low temperature reacts with nitroarenes, nucleophilic substitution of ortho
hydrogen9 leads to N-aryl-2-nitrosoanilines as ultimate products.10 These compounds were
then found to be versatile starting materials for the synthesis of various nitrogen heterocyclic
systems.11 Particularly, cyclization to phenazine derivatives can be, under selected reaction
conditions, accomplished efficiently. Reaction systems such as K2CO3 in MeOH, acetic acid
as a protic acid, and N,O-bis(trimethylsilyl)acetamide (BSA) as a silylating agent were found
to be effective in that respect.12 The latter, known for its promoting role in the formation of
nitrogen heterocycles, apparently proceeding via intermediate nitrosoarenes,13 was found to
be the most reliable and selective.12, 14
On the other hand, despite the high yields of the products, we have noticed remarkable
differences in rates of the reactions for various starting materials. It seems to be important for
the practical synthesis of phenazine derivatives to correlate the speed of the reaction with the
structure of the starting nitrosoaniline, in order to determine the limits of their practical
applications, and to shed light on the mechanism of the cyclization.
2. Results and Discussion.
In order to attain the above goal a number of suitable nitrosoanilines 1 were synthesized. A
few typical substituents were selected and placed in position 5 (substituent X) or in position 4’
3

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(substituent Y) of 1 (Table 1). Their number was limited but their properties range from
electron-withdrawing to electron-donating. The reactions were carried out under standard
conditions (see experimental part) and monitored by TLC up to the apparent disappearance of
the starting material spot visible under UV lamp. Standard work-up allowed to determine the
yield of the product, thus, to verify conversion of the reaction. The amount of 1, if recovered,
did not exceed 5%. Because of the procedure used it is obvious that the results are rough, and
that they are not suitable for kinetic estimations or calculations. Nevertheless, due to very
broad range of the observed reaction times and their monotonic, strong dependence on the
electronic properties of the substituents, the results are enlightening, and provide information
about the course of the reaction under consideration.
Table 1
Cyclization of nitrosoanilines 1 to phenazine derivatives 2
R
R
Y
NO
BSA
N
Y
DMF, r.t.
X
N
N
H
X
1
2
Nitrosoaniline
Phenazine
Yieldb %
2
Entry
R
X
Y
Reaction timea h
1
1
2
3
4
5
6
H
H
H
H
H
H
CF3
H
Cl
Cl
Cl
Cl
Cl
Cl
Cl
0.5
23
48
82
90
89
87
92
1a
1b
1c
1d
1e
1f
2a
2b
2c
2d
2e
2f
F
48
OMe
NMe2
480
360c
traces
7
8
9
H
H
H
H
Cl
Cl
Cl
Cl
NMe2
OMe
H
0.5
0.5
48
90
86
93
85
1g
1h
1i
2f
2e
2b
2g
10
CN
360
1j
11
12
13
Cl
Cl
Cl
Cl
Cl
Cl
OEt
Cl
CN
0.5
36
384
91
87
77
1k
1l
1m
2h
2i
2j
a Reaction was carried out until 1 apparently disappeared on TLC.
b Isolated yield.
c The reaction was too slow to be continued.
Cyclization of 2-nitrosoanilines possessing different substituents X at position 5 (1a-f) is quite
fast for a strong electron-withdrawing group X = CF3, slower for weaker EWG such as
halogens, and very slow for X = EDG which is able to donate electron pairs. The differences
4

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are huge, so that N-(4-chlorophenyl)-5-dimethylamino-2-nitrosoaniline (1f) practically did not
react at all under the conditions applied.
The results collected in Table 1 may be specially helpful for designing of the synthesis of
specific phenazine derivatives. Formally any unsymmetrically substituted phenazine can be
obtained from two, conversely substituted N-aryl-2-nitrosoanilines.12 As a consequence, for
the synthesis of particular phenazine the most convenient way can be chosen. Phenazine 2f
could not be easily obtained from 1f because the reaction was extremely slow (Table 1, entry
6). However, starting from isomeric nitrosoaniline 1g the target phenazine can be obtained
quickly and in high yield (entry 7). Similar considerations apply for other substituents with
strong electronic effects.
In order to explain the differences in the reaction rates, a general mechanistic scheme of the
reaction can be proposed (Scheme 1)
O
Me3Si
O
N
O
N
SiMe3
H
N
BSA
N
H
II
N
H
N
+
+
H
I
1
OSiMe3
N
N
-H+
- Me3SiOH
N
H
N
III
2
Scheme 1 Proposed mechanistic scheme for the formation of phenazines from N-aryl-2-
nitrosoanilines in the presence of BSA.
The electron rich oxygen atom of the nitroso group, additionally enriched by the ortho-amino
group, is initially silylated by BSA to form first intermediate structure I comprising positively
charged iminium group, an ortho-quinoid structure of the nitrosobenzene ring and a silylated
oxime function. This reversible step is followed by irreversible aromatization of intermediate
II and the reaction is concluded by elimination of trimethylsilanol.
Formation of II from I can also proceed in a reverse order, i.e. by reversible intramolecular
addition of the nitrogen to the aryl ring followed by silylation of the oxygen atom.15 While we
could not distinguish these alternatives, further considerations based on the presented
tentative scheme can be applicable essentially for both of them.
The main question is which step is the slowest, thus, responsible for the observed reaction
rates. Attempts to isolate possible intermediates (I - III in Scheme 1) were unsuccessful.
Thus, in order to answer this question the kinetic isotope effect (KIE) in the reaction of 2’-
monodeuterated nitrosoaniline, in which the competitive cyclization at deuterated position 2’
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and non-deuterated position 6’ occurs, was determined. The model 5-chloro-N-(2-deuterio-4-
methoxyphenyl)-2-nitrosoaniline (1h-D) was cyclized under standard conditions producing
deuterated and non-deuterated phenazines 2e-D and 2e respectively (Scheme 2).
NO
N
N
OMe
BSA
Cl
NH
D
H
Cl
DMF, r.t.
H/D
1h-D
2e, 2e-D
OMe
Scheme 2 Cyclization of mono-deuterated nitrosoaniline.
The obtained phenazine was found to be deuterated in 39% (by 1H NMR). Taking into
calculations a purity of starting 1h-D the observed kH/kD = 0.91. The lack of primary isotope
effect clearly indicates that the elimination step is not the rate-limiting step. Moreover, the
observed kH/kD value may reflect secondary KIE caused by the change of the ring carbon
atom hybridization from sp2 to sp3 during the addition step. Thus, the effect of substituents on
the reaction rates can be attributed to their influence on the intramolecular addition step, and
can be explained as follow (Figure 1). Strong conjugation of the lone electron pair of X
(structure IV) greatly reduces positive charge on the iminium nitrogen and consequently also
electrophilicity of the N-aryl ring (structure V). Conversely, electron-withdrawing substituents
X enhance reactivity of that ring while does not affect nucleophilicity of the oxime nitrogen
atom, because of a lack of conjugation.
SiMe
O
N
3
OSiMe3
N
+
X
N
H
X
N
H
+
IV
V
Figure 1 Effect of 5-X substituent on the iminium nitrogen atom.
The opposite effect of the substituent Y, para to the amine nitrogen in the N-aryl ring (Table
1, entries 7-13), may be surprising when assuming that N-aryl ring undergoes a nucleophilic
addition of the oxime nitrogen.
OSiMe3
N
O
N
SiMe3
-
Y
+
Y
X
N
H
X
N
H
+
+
VI
VII
Figure 2 Effect of the conjugation of donor substituent Y on the iminium nitrogen atom.
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However, because of the extensive system of conjugated multiple bonds (VI in Figure 2),
donating effect of Y can be transmitted through the molecule, and enrich electron density on
the oxime nitrogen atom. At the same time the N-aryl ring become more electrophilic (VII).
Contrary, the EWG substituent at 4’ makes the oxime nitrogen less nucleophilic (Figure 3).
OSiMe3
N
OSiMe3
-
+
CN
CN
N
X
N
H
X
N
H
+
+
VII
IX
Figure 3 Effect of the EWG on the nucleophilicity of the oxime nitrogen atom.
The role of the conjugation of Y can be verified by changing its position from 4’ to 3’, where
the effect on the amine nitrogen is only inductive. Thus, nitrosoanilines 1n-r, substituted at
position 2’ with different groups Y, including CN and OMe groups, were selected and
cyclized as previously (Table 2). Since all of them possess two reactive positions in the
arylamine ring, two isomeric phenazines were expected in each reaction.
Table 2 Cyclization of 3'-substituted nitrosoanilines 1n-r.
Y
O
N
Y
N
N
BSA
+
DMF, r.t.
N
N
N
H
Y
1
3
4
Nitrosoaniline
Phenazines
Reaction
timea h
18
Entry
Y
3:4b Total Yieldc %
1
3, 4
1
2
3
4
5
OMe
3a, 4a 84:16
3b, 4b 83:17
3c, 4c 84:16
3d, 4d 60:40
3e, 4e 83:17
62%d
80%
75%
75%
78%
1n
Me
Cl
F
22
24
46
48
1o
1p
1q
1r
CN
a Reaction was carried out until 1 apparently disappeared on TLC.
b Determined by GC.
c Isolated yield.
d Crude 1n was used because of its instability.
Under standard reaction conditions, the isomeric phenazines were formed in a similar ratio,
regardless of the nature of Y. The more significant observation was that the reaction times,
roughly estimated as previously, were also close to each other (Table 2). Although 1r (Y =
CN) cyclizes slower then 1n (Y = OMe), the difference is much smaller than in the case when
Y was located in conjugated position 4 (Table 1, entries 8 and 11). This fact seems to support
the above mechanistic considerations.
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3. Conclusion
Substituted N-aryl-2-nitrosoanilines efficiently cyclize in the presence of N,O-
bis(trimethylsilyl)acetamide (BSA) at room temperature, but the reaction times differ
depending on the substituents and their position in both aromatic rings. EWG substituents
impede the reaction when located at 4' position, but they strongly accelerate the process when
located at position 5, i.e. para to the nitroso group. The effect of EDG is just opposite. This
can be attributed to the mesomeric effects of substituents, which determine the rate of the
addition of the nitrogen atom of the nitroso/oxime group, to the side phenyl ring. The
observed differences in the reaction rates may significantly help in selecting suitable isomeric
nitrosoaniline for the synthesis of desired phenazine derivative.
4. Experimental Section
4.1. General
1H and 13C NMR spectra were recorded on a Varian Mercury 500 instruments at 298 K.
Chemical shifts are expressed in ppm referred to TMS (1H NMR at 500 MHz,13C NMR at 125
MHz), coupling constants in Hertz. IR spectra were recorded with a FT/IR Jasco 6200
spectrometer. Mass spectra (EI, 70 eV or ESI in MeOH) were obtained on an AutoSpec
Premier and an API 365 spectrometers. Qualitative UV–vis spectra were recorded using
MeCN as solvent, range 900.00 to 190.04 nm. GC analyses were performed on a Hewlett
Packard HP6890 GC system with HP5 column and FID (carrier gas – helium). Silica gel
Merck 60 (230-400 mesh) was used for column chromatography. THF was distilled from
sodium/benzophenone ketyl prior to use. DMF was dried over CaH2, distilled and stored over
molecular sieves.
The following nitrosoanilines were obtained as described previously: 1a, 1j16; 1b-d, 1k, 1l10b;
1e,17 1h,18 1i,11d 1m19 and 1n.12 2-Deuterio-4-methoxyanilinene was prepared according to the
reported method.20 Phenazines 2b,12 2c,10a 2d,12 2i,14 3a,12 3c,12 4a12 and 4c12 were identical
with those obtained and described earlier.
4.2. Preparation of nitrosoanilines 1.
4.2.1. Representative procedure:
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N-(5-Chloro-2-nitrosophenyl)-N-(4-dimethylaminophenyl)amine (1g). To a cooled solution of
t-BuOK (672 mg, 6.00 mmol) in DMF (12 mL) was added dropwise at –65 °C a solution of 4-
(dimethylamino)aniline (272 mg, 2.00 mmol), then 4-chloronitrobenzene (315 mg, 2.00
mmol) in DMF (2 mL each). The mixture was stirred at this temperature for 40 min. The
reaction mixture was then poured into a concentrated NH4Cl solution (ca. 50 mL) and
extracted with EtOAc. The extract was washed thoroughly with water and brine, and dried
with Na2SO4. After evaporation, the crude product was subjected to column chromatography
(SiO2, hexane/toluene) to isolate 1g. Dark solid; mp 177-178 °C; Yield 176 mg (32%); IR
(KBr) νmax = 3087, 2882, 2798, 1603,1520,1352, 1146, 1104, 942, 808 cm-1; UV–vis (MeCN)
λmax 483.75, 304.93, 263.30, 239.33, 203.03 nm; 1H NMR (500 MHz, CDCl3): δ = 3.00 (s, 6
H), 6.73-6.76 (m, 2 H), 6.87 (d, J = 8.5 Hz, 1 H), 6.98 (d, J = 1.9 Hz, 1 H), 7.06-7.12 (m, 2
H), 8.66 (br s, 1 H), 12.33 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 40.5, 112.9, 114.8,
118.1, 124.4, 126.4, 134.9, 142.0, 144.3, 149.5, 155.0; MS (EI, 70 eV): m/z (%) 275 (52), 263
(13), 258 (100), 246 (34); HRMS (EI): m/z calcd for C14H1435ClN3O: 275.0825; found:
275.0814.
4.2.2. Nitrozoanilines 1o-1q were obtained according to the representative procedure (see
above), except that THF was used instead of DMF and the reaction was carried out at –78 oC.
4.2.2.1. N-(3-Methylphenyl)-N-(2-nitrosophenyl)amine (1o). Dark red oil; Yield 212 mg
(50%); IR (film): νmax 3041, 2920, 1605, 1568, 1509, 1094, 757 cm-1; UV–vis (MeCN) λmax
477.67, 300.33, 267.67, 249.00, 191.67 nm; 1H NMR (500 MHz, CDCl3): δ = 2.37 (s, 3 H),
6.99 (t, J = 7.4 Hz, 1 H), 7.05-7.09 (m, 3 H), 7.14-7.18 (m, 1 H), 7.26-7.31 (m, 1 H), 7.32-
7.37 (m, 1 H), 8.69 (br s, 1 H), 12.07 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 21.3,
115.3, 117.7, 121.8, 125.3, 127.1, 128.7, 129.4, 136.9, 137.9, 139.7, 156.7, one missing
signal; MS (EI, 70 eV): m/z 212 (7), 211 (16), 195 (100), 181 (37), 180 (36), 167 (34); HRMS
(EI): m/z calcd for C13H11N2O [M-1]+: 211.0871; found: 211.0864.
4.2.2.2. N-(3-Chlorophenyl)-N-(2-nitrosophenyl)amine (1p). Dark crystals; mp 78-79 °C;
Yield 242 mg (52%); IR (film): νmax 3070, 1589, 1565, 1506, 1477, 1366, 1343, 1136, 1090,
757 cm-1; UV–vis (MeCN) λmax 469.10, 298.60, 271.63, 193.37 nm; 1H NMR (500 MHz,
CDCl3): δ = 7.06 (t, J = 7.6 Hz, 1 H), 7.14-7.25 (m, 3 H), 7.27-7.30 (m, 1 H), 7.34 (t, J = 8.1
Hz, 1 H), 7.36-7.44 (m, 1 H), 8.68 (br s, 1 H), 11.72 (br s, 1 H); 13C NMR (125 MHz, CDCl3):
δ = 114.9, 118.4, 118.5, 122.5, 124.4, 126.1, 130.6, 132.6, 135.2, 138.1, 138.7, 156.7; MS
(EI, 70 eV): m/z (%) 233 (5), 232 (7), 215 (100), 201 (45), 197 (15), 167 (53), 166 (24);
35
HRMS (EI): m/z calcd for C12H9 ClN2O: 233.0482; found: 233.0477.
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4.2.2.3. N-(3-Fluorophenyl)-N-(2-nitrosophenyl)amine (1q). Dark oil; Yield 233 mg (54%);
IR (film): νmax 3071, 1604, 1572, 1510, 1486, 1386, 1343, 1142, 1094, 756 cm-1; UV–vis
(MeCN) λmax 471.43, 298.27, 268.30, 220.35, 191.04 nm; 1H NMR (500 MHz, CDCl3): δ =
6.91-6.96 (m, 1 H), 6.96-7.02 (m, 1 H), 7.03-7.07 (m, 2 H), 7.23 (d, J = 8.8 Hz, 1 H), 7.32-
7.44 (m, 2 H), 8.66 (br s, 1 H), 11.73 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 111.3 (d,
JCF = 23.6 Hz), 112.8 (d, JCF = 21.3 Hz), 114.9, 118.4, 119.8 (d, JCF = 3.4 Hz), 130.8 (d, JCF =
9.3 Hz), 132.5, 138.1, 139.0 (d, JCF = 9.8 Hz), 156.7, 163.2 (d, JCF = 247.9 Hz), one signal
missing; MS (EI, 70 eV): m/z (%) 217 (1), 216 (8), 199 (100), 185 (89); HRMS (EI): m/z
calcd for C12H10FN2O: 217.0777; found: 217.0774.
4.2.2.4. N-(3-Cyanophenyl)-N-(2-nitrosophenyl)amine (1r). The compound was obtained
according to the representative procedure (see above), except that THF was used instead of
DMF and the reaction was started at –78 oC and after 30 min the cooling bath was removed
and the reaction was allowed to reach the room temperature. Dark red solid; mp 119 °C; Yield
241 mg (54%); IR (KBr): νmax 3314, 3068, 2230, 1583, 1511, 1135, 1093 cm-1; UV–vis
(MeCN) λmax 467.10, 273.63, 223.01, 195.70 nm; 1H NMR (500 MHz, CDCl3): δ = 7.10-7.15
(m, 1 H), 7.19 (d, J = 8.4 Hz, 1 H), 7.44-7.49 (m, 1 H), 7.5-7.54 (m, 3 H), 7.61 (s, 1 H), 8.68
(br s, 1 H), 11.52 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 113.9, 114.5, 117.9, 119.2,
119.3, 127.0, 128.4, 129.1, 130.7, 130.8, 138.3, 138.9, 156.8; MS (EI, 70 eV): m/z (%) 223
(19), 209 (13), 206 (100), 192 (95); HRMS (EI) m/z calcd for C13H9N3O: 223.0746; found:
223.0739.
4.2.2.5. N-(4-chlorophenyl)-N-[5-(dimethylamino)-2-nitrosophenyl]amine (1f).
To a solution of N-(4-chlorophenyl)-N-(5-fluoro-2-nitrosophenyl)amine10b (752 mg, 3.00
mmol) in EtOH (25 mL) was added a 33% solution of Me2NH in EtOH (2,9 mL, 15.0 mmol)
and the mixture was stirred at room temperature for 4 h then it was poured into water and
extracted with EtOAc. The extract was washed with water, brine and dried with Na2SO4.
After evaporation, the crude product, 730 mg (yield 88%) was pure enough for the cyclization
step. Dark crystals; mp 170-173 °C; IR (KBr): νmax 3008, 2919, 1624, 1497, 1328, 1136, 912,
805, 622 cm-1; UV–vis (MeCN) λmax 394.84, 276.29, 221.68, 191.71 nm; 1H NMR (500
MHz, CDCl3): δ = 3.10 (s, 6 H), 5.96 (d, J = 2.5 Hz, 1 H), 6.49 (dd, J = 9.5, 2.5 Hz, 1 H),
7.21-7.24 (m, 2 H), 7.33-7.36 (m, 2 H), 8.20 (d, J = 9.5 Hz, 1 H), 13.04 (s, 1 H); 13C NMR
(125 MHz, CDCl3): δ = 89.0, 106.6, 125.8, 129.6, 130.7, 136.7, 138.5, 142.0, 151.8, 155.9;
MS (EI, 70 eV): m/z (%) 275 (100), 258 (66), 244 (69). HRMS (EI): m/z calcd for
C14H1435ClN3O: 275.0825; found: 275.0811.
10

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4.2.2.6. N-(5-Chloro-2-nitrosophenyl)-N-(2-deuterio-4-methoxyphenyl)amine (1h-D). The
compound was obtained starting from 2-deuterio-4-methoxyaniline (89% D, based on MS),
according to the procedure described earlier for the non-deuterated product.17 The crude 1h-D
was then used for the cyclization reaction. Isotope purity (82% D) was determined by the 1H
NMR spectrum of a purified sample. 1H NMR (500 MHz, DMSO-d6): δ = 3.80 (s, 3 H), 6.86-
6.90 (m, 1 H), 6.96 (d, J = 1.8 Hz, 1 H), 7.03-7.06 (m, 2 H), 7.33-7.36 (m, 1.18 H), 7.88 (br s,
1 H), 11.53 (s, 1 H).
4.3. Cyclization of nitrosoanilines 1. General procedure.
To a solution of 1 (0.50 mmol) in dry DMF (8 mL) was added BSA (0.61 mL, 2.50 mmol)
and the mixture was stirred at room temperature. The reaction was monitored by tlc (SiO2
plate, hexane/EtOAc 4:1) of small samples of the mixture quenched with water and extracted
with EtOAc. After the spot of 1 disappeared, or was only slightly visible (see Table 1 and 2
for the rough reaction times), water (4 mL) was added and the mixture was stirred for 10 min.
In case a solid product precipitate forming, it was filtered off, washed with water and a small
amount of cold MeOH, then dried on air. Otherwise the reaction mixture was poured into
water and extracted with EtOAc. The extract was washed with water and brine and dried with
Na2SO4. After evaporation, the residue was purified by column chromatography (SiO2,
hexane/EtOAc 4:1) to obtain pure phenazine 2. When two isomers of the product was formed
(3 and 4) they were separated and isolated in this way.
4.3.1. 2-Chloro-7-(trifluoromethyl)phenazine (2a). Colorless crystals, mp 159-160 °C (i-
PrOH); Yield 115 mg (82%); IR (film): νmax 3058, 2996, 1332, 1150, 1122, 823 cm-1; UV–vis
(MeCN) λmax 368.86, 251.98, 211.36 nm; 1H NMR (500 MHz, CDCl3): δ = 7.82 (dd, J = 9.2,
2.1 Hz, 1 H), 7.98 (dd, J = 9.0, 1.7, Hz, 1H), 8.22 (d, J = 9.2 Hz, 1 H), 8.27 (d, J = 2.1 Hz, 1
H), 8.35 (d, J = 9.0 Hz, 1 H), 8.57 (br s, 1 H); 13C NMR (125 MHz, CDCl3): δ = 123.4 (q, JCF
= 272.8 Hz), 128.1, 128.2, 131.14, 131.15, 131.9, 132.2, 132.8, 138.0, 141.9, 142.6, 144.1,
144.3; MS (EI, 70 eV): m/z (%) 284 (32), 283 (16), 282 (100) [M+], 247 (14), 227 (3); HRMS
35
(EI): m/z calcd for C13H6 ClF3N2: 282.0172; found: 282.0164.
4.3.2. 2-Chloro-7-methoxyphenazine (2e). Yellow crystals, mp 162-165 °C (i-PrOH); [lit.21
173-174 °C (EtOH)]; Yield 112 mg (92%); IR (film): νmax 3072, 2966, 2831, 1632, 1474,
1424, 1298, 1217, 813 cm-1; UV–vis (MeCN) λmax 394.17, 351.55, 259.31, 218.68 nm; 1H
NMR (500 MHz, CDCl3): δ = 4.02 (s, 3 H), 7.36 (d, J = 2.6 Hz, 1 H), 7.51 (dd, J = 9.5, 2.6
Hz, 1 H), 7.72 (dd, J = 9.2, 2.2 Hz, 1 H), 8.04 (d, J = 9.5 Hz, 1 H), 8.09 (d, J = 9.2 Hz, 1 H),
8.18 (d, J = 2.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ = 55.9, 104.5, 127.1, 128.0, 130.1,
11

ACCEPTED MANUSCRIPT
130.6, 131.7, 134.8, 141.1, 141.7, 141.8, 145.0, 161.5; MS (EI, 70 eV): m/z (%) 246 (33), 245
35
(15), 244 (100) [M+], 203 (20), 201 (60), 179 (2); HRMS (EI): m/z calcd for C13H9 ClN2O:
244.0403; found: 244.0394.
4.3.3. 2-Chloro-7-dimethylaminophenazine (2f). Yield 116 mg (90% from 1g); Orange
crystals, mp 210 °C (i-PrOH) (lit.6a 209-210 °C); IR (KBr): νmax 3062, 2894, 2800, 1622,
1488, 1424, 1345, 938, 810 cm-1; UV–vis (MeCN) λmax 492.74, 360.87, 289.28, 236.33 nm;
1H NMR (500 MHz, CDCl3): δ = 3.22 (s, 6 H), 7.03 (d, J = 2.7 Hz, 1 H), 7.61 (dd, J = 9.6,
2.7 Hz, 1 H), 7.66 (dd, J = 9.2, 2.2 Hz, 1 H), 8.00 (d, J = 9.2 Hz, 1 H), 8.01 (d, J = 9.6 Hz, 1
H), 8.12 (d, J = 2.2 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ = 40.4, 102.5, 123.4, 128.0,
129.6, 130.1, 131.3, 132.9, 139.9, 140.8, 142.4, 145.5, 151.1; MS (EI, 70 eV): m/z (%) 259
(33), 257 (100) [M+], 216 (4), 214 (11); HRMS (EI): m/z calcd for C14H1235ClN3: 257.0720;
found: 257.0711.
4.3.4. 2-Chloro-7-cyanophenazine (2g). Yield 102 mg (85%); Yellow solid, mp 315-318 °C
dec. [lit.22 318.5-319.5 °C (EtOH)]; IR (ATR): νmax 3056, 2924, 2224, 1504, 1414, 1059, 820
cm-1; UV–vis (MeCN) λmax 377.33, 260.67, 213.67 nm; 1H NMR (500 MHz, CDCl3):
δ =
7.85 (dd, J = 9.3, 2.2 Hz, 1 H), 7.94 (dd, J = 9.0, 1.8 Hz, 1 H), 8.24 (d, J = 9.3 Hz, 1 H), 8.28
(d, J = 2.2 Hz, 1 H), 8.34 (d, J = 9.0 Hz, 1 H), 8.67 (d, J = 1.8 Hz, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 114.9, 118.0, 127.1, 130.9, 131.3, 132.3, 135.0, 136.6, 137.8, 139.6, 141.1,
144.3, 145.1; MS (EI, 70 eV) m/z (%) 240 (44), 239 (100), 204 (26), 178 (3), 154 (3), 127 (4);
35
HRMS (EI): m/z calcd for C13H6 ClN3: 239.0250; found: 239.0245.
4.3.5. 1,3-Dichloro-8-ethoxyphenazine (2h). Yield 133 mg (91%); Pale green crystals, mp
200-202 °C (i-PrOH); IR (film): νmax 3062, 2985, 2910, 2869, 1628, 1470, 1204, 814 cm-1;
UV–vis (MeCN) λmax 407.16, 355.88, 264.97, 219.35, 191.71, 190.71 nm; 1H NMR (400
MHz, CDCl3):
H), 7.54 (dd, J = 9.4, 2.7 Hz, 1 H), 7.87 (d, J = 2.1 Hz, 1 H), 8.05 (d, J = 9.4 Hz, 1 H), 8.12
(d, J = 2.1 Hz, 1 H); 13C NMR (100 MHz, CDCl3):
= 14.5, 64.6, 105.3, 127.3, 128.4, 130.2,
δ = 1.55 (t, J = 7.0 Hz, 3 H), 4.26 (q, J = 7.0 Hz, 2 H), 7.46 (d, J = 2.7 Hz, 1
δ
130.7, 133.2, 133.5, 138.5, 141.3, 141.7, 145.1, 161.3; MS (EI, 70 eV) m/z (%) 292 [M+] (50),
264 (100); HRMS (EI): calcd for C14H1035Cl2N2O: 292.0170; found: 292.0179.
4.3.6. 1,3-Dichloro-8-cyanophenazine (2j). Yield 105 mg (77%); Yellow crystals, mp 250-
251 °C; IR (ATR): νmax 3098, 3068, 3035, 2231, 1585, 1502, 1389, 984 cm-1; UV–vis
(MeCN) λmax 377.19, 265.30, 212.69, 191.38 nm; 1H NMR (500 MHz, CDCl3):
(m, 2 H), 8.14 (d, J = 2.1 Hz, 1 H), 8.27 (d, J = 8.9 Hz, 1 H), 8.71 (d, J = 1.5 Hz, 1 H); 13C
δ = 7.89-7.94
12

ACCEPTED MANUSCRIPT
NMR (125 MHz, CDCl3):
δ
= 114.7, 117.6, 127.3, 131.1, 131.3, 132.2, 134.9, 136.9, 137.8,
139.8, 141.5, 144.4, 144.7; MS (EI, 70 eV) m/z (%) 273 [M+] (100), 238 (22), 203 (5), 178
35
(3), 152 (10); HRMS (EI): m/z calcd for C13H5 Cl2N3: 272.9861; found: 272.9857.
4.3.7. 7-Chloro-2-methoxyphenazine (2e-D) and 8-chloro-2-deuterio-4-methoxyphenazine
(2e). 1H NMR (500 MHz, CDCl3): δ = 4.02 (s, 3 H), 7.36 (d, J = 2.6 Hz, 1 H), 7.51-7.54 (m, 1
H), 7.73 (dd, J = 9.2, 2.2 Hz, 1 H), 8.05-8.08 (m, 0.61 H), 8.09 (d, J = 9.2 Hz, 1 H), 8.18 (d, J
= 2.2 Hz, 1 H).
4.3.8. 2-Methylphenazine (3b). Yield 64 mg (66%); Greenish crystals, mp 117-119 °C (i-
PrOH) (lit.23 117-119 oC); HRMS (EI): m/z calcd for C13H10N2: 194.0844; found: 194.0840.
4.3.9. 1-Methylphenazine (4b). Yield 13 mg (14%) Yellowish crystals, mp 105-108 °C (i-
PrOH) (lit.24 106-109 oC); HRMS (EI): m/z calcd for C13H10N2: 194.0844; found: 194.0849.
4.3.10. 2-Fluorophenazine (3d). Yield 62 mg (63%); Yellow crystals; mp 139-141 oC (i-
PrOH) (lit23 180-182 oC); 1H NMR (500 MHz, CDCl3):
δ = 7.63-7.68 (m, 1 H), 7.82-7.89 (m,
3 H), 8.2-8.28 (m, 3 H); 13C NMR (125 MHz, CDCl3): δ = 111.6 (d, JCF = 21 Hz), 122.6 (d,
JCF = 28.3 Hz), 129.2, 129.8, 130.4, 131.2, 132.1 (d, JCF = 10.4 Hz), 141.0, 142.9, 143.7,
143.8 (d, JCF = 13.3 Hz), 163.0 (d, JCF = 256.0 Hz); MS (EI, 70 eV): m/z (%) 198 (100) [M+],
197 (42), 171 (11), 150 (2), 145 (4); HRMS (EI): m/z calcd for C12H7FN2: 198.0593; found:
198.0597.
4.3.11. 1-Fluorophenazine (4d). Yield 12 mg (10%);Yellow crystals; mp 125-126 °C (i-
PrOH) [lit.25 208-209 oC (EtOH)]; IR (film): νmax 3046, 3021, 1519, 1060, 758, 737 cm-1;
UV–vis (MeCN) λmax 361.21, 246.65, 245.99, 244.66, 203.36 nm; 1H NMR (500 MHz,
CDCl3): δ = 7.47-7.53 (m, 1 H), 7.73-7.79 (m, 1 H), 7.85-7.89 (m, 2 H), 8.04-8.08 (m, 1 H),
8.21-8.26 (m, 1 H), 8.32-8.37 (m, 1 H); 13C NMR (125 MHz, CDCl3): δ = 112.9 (d, JCF =
18.5 Hz), 125.6 (d, JCF = 4.6 Hz), 129.4 (d, JCF = 8.7 Hz), 129.6, 130.0, 131.1, 131.4, 135.1
(d, JCF = 13.3 Hz), 143.0, 143.8, 144.0, 157.0 (d, JCF = 262.4 Hz); MS (EI, 70 eV): m/z (%)
198 (100) [M+], 197 (30), 179 (3), 171 (9), 150 (2); HRMS (EI): m/z calcd for C12H7FN2:
198.0593; found: 198.0602.
4.3.12. 2-Cyanophenazine (3e). Yield 66 mg (65%);Yellow crystals; mp 235-236 °C (i-PrOH)
(lit.23 212-214 oC); IR (film): νmax 3053, 3016, 2224, 908, 834, 758, 631 cm-1; UV–vis
(MeCN) λmax 367.20, 257.98, 208.69 nm; 1H NMR (500 MHz, CDCl3):
δ = 7.9-7.98 (m, 3 H),
8.26-8.31 (m, 2 H), 8.37 (d, J = 9.1 Hz, 1 H), 8.69 (d, J = 1.3 Hz, 1 H); 13C NMR (125 MHz,
CDCl3): δ = 113.8, 118.0, 129.7, 129.8, 130.1, 131.5, 131.8, 132.4, 136.7, 141.9, 143.8,
13

ACCEPTED MANUSCRIPT
144.5, 144.7; MS (EI, 70 eV): m/z (%) 205 (100) [M+], 204 (23), 179 (5), 178 (8); HRMS
(EI): m/z calcd for C12H7N3: 205.0640; found: 205.0635.
4.3.13. 1-Cyanophenazine (4e). Yield 14 mg (13%); Orange solid, mp 166-167 °C (lit.22 170-
172 oC); IR (film): νmax 3335, 3059, 2229, 1519, 1325, 743 cm-1; UV–vis (MeCN) λmax
364.87, 247.32, 200.70 nm; 1H NMR (500 MHz, CDCl3):
δ = 7.90 (dd, J = 8.9, 7.1 Hz, 1 H),
7.93 -7.97 (m, 2 H), 8.26-8.29 (m, 1 H), 8.31 (dd, J = 7.1, 1.3 Hz, 1 H), 8.39-8.44 (m, 1 H),
8.51 (dd, J = 8.9, 1.3 Hz, 1 H); 13C NMR (125 MHz, CDCl3): δ = 113.6, 116.4, 129.0, 129.7,
130.2, 131.9, 132.0, 135.0, 137.1, 142.3, 144.1, 144.4, 148.2; MS (EI, 70 eV): m/z (%) 205
(100) [M+], 204 (16), 179 (5), 178 (6); HRMS (EI): m/z calcd for C12H7N3: 205.0640; found:
205.0634.
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Captions:
Scheme 1.
Proposed mechanistic scheme for the formation of phenazines from N-aryl-2-nitrosoanilines
in the presence of BSA.
Scheme 2.
Cyclization of mono-deuterated nitrosoaniline.
Figure 1.
Effect of 5-X substituent on the iminium nitrogen atom.
Figure 2.
Effect of the conjugation of donor substituent Y on the iminium nitrogen atom.
16

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Figure 3.
Effect of the EWG on the nucleophilicity of the oxime nitrogen atom.
17