Synthesis and anion recognition studies of novel 5,5-dioxidophenothiazine- 1,9-diamides

Article abstract of DOI:10.1016/j.tet.2012.06.070

Novel 5,5-dioxidophenothiazine-1,9-diacetamide and -dibenzamide receptor molecules were prepared starting from commercially available and relatively cheap chemicals. The anion recognition properties of these two diamides were investigated using UV-vis spectroscopy. Chloride formed a simple hydrogen-bonded complex with the diacetamide receptor, while fluoride, acetate and dihydrogen phosphate deprotonated both sensor molecules. Upon titration with fluoride deprotonation occurred via the formation of [HF₂]^-, and in the case of the diacetamide receptor complexation took place alongside deprotonation.

Full text of DOI:10.1016/j.tet.2012.06.070

Tetrahedron 68 (2012) 7063e7069
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Synthesis and anion recognition studies of novel
5,5-dioxidophenothiazine-1,9-diamides
a
a
,
b
a
c
d
e,f
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ ꢀ
ꢀ
ꢀ
ꢀ
Attila Kormos , Ildiko Moczar , Attila Sveiczer , Peter Baranyai , Laszlo Parkanyi , Klara Toth
Peter Huszthy
,
a,b,
*
ꢀ
a Department of Organic Chemistry and Technology, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
b Research Group for Alkaloid Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
c Department of Spectroscopy, Institute of Molecular Pharmacology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, PO Box 17, H-1525 Budapest, Hungary
d Department of Structural Chemistry, Institute of Organic Chemistry, Research Centre for Natural Sciences, Hungarian Academy of Sciences, PO Box 17, H-1525 Budapest, Hungary
e Research Group for Technical Analytical Chemistry of the Hungarian Academy of Sciences, PO Box 91, H-1521 Budapest, Hungary
f Department of Inorganic and Analytical Chemistry, Budapest University of Technology and Economics, PO Box 91, H-1521 Budapest, Hungary
a r t i c l e i n f o
a b s t r a c t
Article history:
Novel 5,5-dioxidophenothiazine-1,9-diacetamide and -dibenzamide receptor molecules were prepared
starting from commercially available and relatively cheap chemicals. The anion recognition properties of
Received 28 February 2012
Received in revised form 24 May 2012
Accepted 15 June 2012
these two diamides were investigated using UVevis spectroscopy. Chloride formed
a simple
hydrogen-bonded complex with the diacetamide receptor, while fluoride, acetate and dihydrogen
phosphate deprotonated both sensor molecules. Upon titration with fluoride deprotonation occurred via
the formation of [HF2]ꢀ, and in the case of the diacetamide receptor complexation took place alongside
deprotonation.
Available online 23 June 2012
Keywords:
Phenothiazine
Anion recognition
Deprotonation
Ó 2012 Elsevier Ltd. All rights reserved.
1. Introduction
carbamide-based17,19,20 receptors or host molecules containing
heterocycles with slightly acidic NH groups, like pyrrole,21 indole
Anions play an important role in many chemical and biological
processes, so the synthesis and development of anion sensors are of
great importance. Although the first synthetic anion receptors al-
ready appeared in the late 60s,1,2 the development of host mole-
cules for anion recognition was much slower than that for cations.
This can be explained by the properties of anions such as their large
size compared to cations, their occurrence in a wide range of
shapes, their usually high solvation energy and that many of them
are sensitive to pH. However, the field of anion sensors has ex-
panded notably in the past decade.3e9
Many receptors synthesized in the last few years allow optical
detection of anionic species.10e15 The development of colorimetric
sensors is of particular interest, because these so called ‘naked-eye’
sensors can provide immediate qualitative information without the
need for an expensive equipment. In several cases the colour
change is due to the deprotonation of the receptor molecule.
One of the main groups of anion receptors consists of neutral
molecules, which bind anions via hydrogen bond formation (often
accompanied by deprotonation), for example, amide-16e18 and
and carbazole.22
Although in the case of deprotonation the receptor behaves as
an acidebase indicator and selectivity is mainly based on anion
basicity,23,24 the degree of selectivity can be enhanced by varying
the number and the spatial arrangement of the binding sites of the
host.25,26 Several research groups investigated the deprotonation of
different anion sensors. Fabbrizzi and co-workers found that fluo-
ride, acetate and dihydrogen phosphate could deprotonate urea- or
thiourea-containing molecules in two steps via formation of the
[HX2]ꢀ self-complex (where X means the anion in question).23 In
the case of a urea-type receptor containing two naphthaleneimide
units they even observed double deprotonation upon addition of
a large excess of fluoride to the host in DMSO with the formation of
[HF2]ꢀ, while acetate and dihydrogen phosphate could remove only
one proton from the sensor molecule without the formation of
[HX2]ꢀ.27 Gale and co-workers showed that in the cases of some
pyrrolylamidothiourea derivatives only 1 equiv of anion (even for
fluoride) was necessary for the deprotonation of the receptors,
probably due to the spatial arrangement of these molecules, which
could not stabilize the hydrogen-bonded complexes.28 Perez-Casas
ꢀ
and Yatsimirsky found that the deprotonation of thiourea de-
rivatives could be suppressed in the presence of added acetic acid,
* Corresponding author. Tel.: þ36 1 463 1071; fax: þ36 1 463 3297; e-mail
address: huszthy@mail.bme.hu (P. Huszthy).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2012.06.070

7064
A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
and the stability constants of the hydrogen-bonded complexes
could be determined.29
protected by tert-butyl groups to synthesize 1,9-disubstituted de-
rivatives. An improved procedure was elaborated for the prepara-
tion of the reported 3,7-di-tert-butylphenothiazine (7)32 (Scheme
3). Using dichloromethane as solvent instead of tert-butyl chlo-
ride, with a much shorter reaction time (5 min instead of 2 h),
nearly tripled the reported yield without the need for chromatog-
raphy. Di-tert-butylphenothiazine 7 was then nitrated using acetyl
nitrate in dichloromethane. If 2 equiv of acetyl nitrate was used, the
main product was mononitrophenothiazine sulfoxide 8. If
3 equiv of acetyl nitrate was used, the main product was
dinitrophenothiazine sulfoxide 3. In the latter case, the main
by-products were mononitro-sulfoxide 8 and dinitro-sulfone 5.
Mononitro-sulfoxide 8 could be converted into dinitro-sulfoxide 3
using the same procedure again. Dinitrophenothiazine sulfoxide 3
was then oxidized using hydrogen peroxide in acetic acid to give
dinitrophenothiazine sulfone 5. As in the preparation of
dinitro-sulfoxide 3, one of the main by-products was dinitro-
sulfone 5, crude dinitro-sulfoxide 3 could also be used for the
preparation of dinitro-sulfone 5 with a somewhat higher overall
yield (Scheme 3).
Phenothiazine 5,5-dioxide has a pKa value of 15.75 in DMSO30
between the pKa values of N,N0-diphenylurea and N,N0-diphe-
nylthiourea (19.55 and 13.4, respectively, in DMSO),31 so in-
vestigation of deprotonation and hydrogen bond formation of
receptors containing phenothiazine-dioxide subunits towards basic
anions is of particular interest.
In this paper we report the synthesis of novel 5,5-
dioxidophenothiazine-1,9-diamides (1 and 2, Fig. 1) and studies
of their behaviour towards different anions in acetonitrile.
The crystal structures of phenothiazine derivatives 1, 3 and 5
were determined by X-ray crystallography. Diacetamide 1 formed
chains held together by NeH/O type hydrogen bonds due to the
acidic NH (N10, N11 and N110), sulfonyl (O1) and one of the carbonyl
(O3) groups of the receptor molecule. An intramolecular NeH/N
type hydrogen bond was also formed between the phenothiazine
NH (N10) and one of the amide NHs (N11) and an acetic acid
molecule was linked to the other carbonyl group of diacetamide 1
(O30) by an OeH/O type bond (Fig. 2, Table 1, Table S1, see
Supplementary data). In dinitro compounds 3 and 5 only intra-
molecular NeH/O type hydrogen bonds were present between
the nitro groups and the phenothiazine NH (Figs. S19 and S20,
Tables S1eS3, see Supplementary data).
Fig. 1. Structures of new receptors 1 and 2.
2. Results and discussion
2.1. Synthesis
The synthesis of new diacetamide 1 was carried out in two ways
as outlined in Scheme 1. In the first case, dinitrophenothiazine
sulfoxide 3 was hydrogenated in acetic acid in the presence of
acetic anhydride to give phenothiazine diacetamide 4, which was
then oxidized in acetic acid using hydrogen peroxide in the pres-
ence of acetic anhydride to render 5,5-dioxidophenothiazine
diacetamide 1. In the second case, dinitrophenothiazine sulfone 5
was hydrogenated in acetic acid in the presence of acetic anhydride
to give diacetamide 1.
2.2. Anion recognition studies
The anion recognition ability of receptors 1 and 2 was studied in
acetonitrile towards the tetrabutylammonium salts of fluoride,
Scheme 1. Preparation of receptor 1.
Dibenzamide 2 was prepared as shown in Scheme 2. Dini-
trophenothiazine sulfone 5 was hydrogenated in 95% aqueous
acetic acid to give diaminophenothiazine sulfone 6, which was also
prepared by hydrolyzing diacetamide 1 using 20% aqueous hydro-
chloric acid. Diamine 6 was then acylated in pyridine using benzoyl
chloride to render dibenzamide 2.
chloride, bromide, iodide, hydrogen sulfate, dihydrogen phosphate
and acetate by UVevis spectroscopy.
Fluoride, acetate and dihydrogen phosphate caused large
changes in the spectra of both sensor molecules, while chloride
induced a slight, but significant spectral change only in the case of
receptor 1. The other anions had no effect on the spectra of either
receptor (Fig. 3). Since the deprotonation of neutral anion sensors
may occur in the presence of basic anions as reported in several
Electrophilic aromatic substitution reactions of phenothiazine
take place first in positions 3 and 7, so these positions were

A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
7065
Scheme 2. Preparation of receptor 2.
Scheme 3. Synthesis of nitrophenothiazine derivatives (3, 5 and 8).
Fig. 2. X-ray structure of 1: ORTEP diagram (A, AcOH is omitted for clarity), hydrogen bond interactions indicated by dotted lines (B, non-acidic hydrogens are omitted for clarity).
stoichiometry (Table 2), which suggests that complexation was not
Table 1
significant in these cases, and that deprotonation occurred without
Hydrogen bond geometry for 1
the formation of [HX2]ꢀ.
d(DeH) (A) d(H/A) (A) d(D/A) (A) :(DeH/A) (ꢁ)
ꢁ
ꢁ
ꢁ
D
H
A
However, upon titration of receptor 1 with fluoride the spectral
shift in the range of 270e310 nm, which is characteristic for com-
plexation, also appeared beside the spectrum of the deprotonated
form (Fig. 5). Best fits were obtained when we considered both
processes using 1:1 and 1:2 stoichiometries for the complexation
and the deprotonation, respectively (Table 2). The 1:2 stoichiome-
try of the deprotonation supports the formation of [HF2]ꢀ in ac-
cordance with several examples reported in the literature.23,24 The
only difference between the behaviour of receptor 1 and 2 with
fluoride was the absence of the complexation induced spectral shift
in the case of receptor 2 (Fig. S23, see Supplementary data), which
can be attributed to the more acidic property of the latter
compound.
N10 H10 O3a 0.91
N10 H10 N11 0.91
N11 H11 O1b 0.91
N110 H110 O1b 0.92
2.08
2.41
2.24
2.30
1.85
2.916(2)
2.745(2)
3.101(2)
3.196(2)
2.702(2)
151.8
102.0
157.1
166.6
158.9
O2S
H2O O30
0.89
a
2ꢀx, ꢀy, 1ꢀz.
1ꢀx, 1ꢀy, 1ꢀz.
b
cases in the literature,23,24 we recorded the spectra of the depro-
tonated forms of receptors 1 and 2 using 1,8-diazabicyclo[5.4.0]
undec-7-ene (DBU) as a strong base (Fig. 3). The pKa values were
determined upon titration with triethylamine using UVevis spec-
troscopy (21.76 and 21.29 for 1 and 2, respectively).
Chloride caused only a slight red shift in the absorption spec-
trum of receptor 1 indicating a complexation process (Fig. 6).
In the case of acetate when the complexation induced spectral
shifts did not appear during the titration of neither receptor, we
tried to suppress deprotonation by addition of acetic acid in order
to promote the complex formation as reported in the literature.29
Indeed, the titration of receptor 1 with acetate under these
Addition of fluoride, acetate and dihydrogen phosphate induced
the deprotonation of both of the receptors (Fig. 3). In the case of
acetate and dihydrogen phosphate, the titration series of spectra
did not show spectral changes characteristic to the hydrogen bond
formation between the receptor and the anion (Fig. 4 and Figs. S21
and S22, see Supplementary data). Assuming only a deprotonation
process, the spectra could be fitted satisfactorily using 1:1

7066
A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
Fig. 3. UVevis spectral changes of 1 and 2 (20
m
M, A: 1, B: 2) upon addition of anions (4 equivof Fꢀ, AcOꢀ, H2PO4ꢀ and 100 equivof Clꢀ, Brꢀ, Iꢀ, HSOꢀ4 ) and a base (4 equivof DBU) in MeCN.
Fig. 4. Absorption series of spectra upon titration of 1(20 m
M) with AcOꢀ (0e3 equiv)inMeCN.
Fig. 6. Absorption series of spectra upon titration of 1(20 m
M) with Clꢀ (0e200 equiv) in MeCN.
Table 2
Equilibrium constants of complex formation (K1) and deprotonation (K2) for 1 and 2
with different anions
conditions provided a series of spectra (Fig. 7) very similar to the
one obtained earlier with chloride (Fig. 6), which allowed us to
determine the equilibrium constant of the complex formation
(Table 2). Distinctly, in the case of receptor 2 complexation started
simultaneously with deprotonation (Fig. 7), which can also be
explained by the more acidic property of the latter compound
compared to receptor 1.
1
2
log K1
log K2
log K1
log K2
Fꢀ
5.13
3.83
d
3.52a
5.28
d
d
d
6.05
d
Clꢀ
H2POꢀ4
AcOꢀ
ꢀ1.05
0.67
d
b
ꢀ0.52
0.94
a
Determined upon titration with AcOꢀ in the presence of AcOH.
3. Conclusion
b
The titration series of spectra obtained with AcOꢀ in the presence of AcOH could
not be fitted satisfactorily.
The
synthesis
and
characterization
of
new
5,5-
dioxidophenothiazine-1,9-diamides 1 and 2, and their unreported
precursors have been achieved. The reported 3,7-di-tert-butyl-
phenothiazine (7) was prepared using a new efficient procedure.
Furthermore, nitration of the latter phenothiazine derivative pro-
vides an opportunity for the synthesis of several 1,9-disubstituted
phenothiazines by the transformation of the nitro groups.
We examined the anion recognition properties of new receptors
1 and 2 by UVevis spectroscopy. It was demonstrated that chloride
formed a hydrogen-bonded complex with receptor 1, while fluo-
ride, acetate and dihydrogen phosphate caused the deprotonation
of both sensor molecules. Upon titration with fluoride there was
a difference between receptors 1 and 2, namely beside deproto-
nation, complexation also took place in the case of receptor 1. In
both cases deprotonation occurred with the formation of [HF2]ꢀ.
The results suggest that the spectral shifts of these two re-
ceptors in the presence of more basic anions (fluoride, acetate and
dihydrogen phosphate) are mainly induced by acidebase equilibria.
However, increasing the number of binding sites of the receptor
molecules may enhance the complexation ability to give more
Fig. 5. Absorption series of spectra upon titration of 1(20 m
M) with Fꢀ (0e6 equiv) inMeCN.

A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
7067
Fig. 7. Absorption series of spectra upon titration of 1 and 2 (20 m
M) with AcOꢀ (A: 1, 0e200 equiv, B: 2, 0e160 equiv) in the presence of AcOH (5 mM) in MeCN.
selective behaviour towards different anions. Synthesis of further
phenothiazine-5,5-dioxide derivatives with more binding sites is
currently in progress.
was completed, the catalyst was filtered off, and the solution was
concentrated to one-third of its original volume. The deposited
solid was filtered off to give 1 (9.19 g, 87%) as a white solid.
Mp 305e307 ꢁC (AcOH); Rf 0.28 (silica gel TLC, MeOH/CH2Cl2
1:20); IR (KBr) nmax 3359, 3290, 3052, 2962, 2907, 2871, 1714, 1693,
1613, 1582, 1497, 1420, 1365, 1273, 1240, 1187, 1126, 1095, 1020, 981,
891, 882, 747, 644, 626, 538, 496 cmꢀ1; 1H NMR (300 MHz, DMSO-d6)
4. Experimental
4.1. General
d
1.32 (s,18H, t-Bu), 2.17 (s, 6H, COMe), 7.60 (d, J¼2 Hz, 2H, ArH), 7.70
(d, J¼2 Hz, 2H, ArH), 9.00 (br s, 1H, NH), 10.10 (s, 2H, NH); 13C NMR
Starting materials were purchased from SigmaeAldrich Corpo-
ration unless otherwise noted. Silica gel 60 F254 (Merck) plates were
used for TLC. Ratios of solvents for the eluents are given in volumes
(mL/mL). Solvents were dried and purified according to well-
established methods.33 Evaporations were carried out under re-
duced pressure unless otherwise stated.
Infrared spectra were recorded on a Bruker Alpha-T FT-IR
spectrometer. 1H (500 MHz) and 13C (125 MHz) NMR spectra were
obtained on a Bruker DRX-500 Avance spectrometer. 1H (300 MHz)
and 13C (75 MHz) NMR spectra were obtained on a Bruker 300
Avance spectrometer. Elemental analyses were performed in the
Microanalytical Laboratory of the Department of Organic Chemis-
(75.5 MHz, DMSO-d6)
d 23.15, 30.91, 34.46, 115.07, 121.66, 125.95,
127.64, 130.89, 144.40, 169.72; MS calcd for C24H31N3O4S: 457.2.
Found (MꢀH)ꢀ: 456.2. Anal. Calcd for C24H31N3O4S$H2O: C, 60.61; H,
6.99; N, 8.84; S, 6.74. Found: C, 60.72; H, 6.81; N, 8.72; S, 6.85.
4.2.2. Starting from phenothiazine diacetamide 4. To a vigorously
stirred suspension of phenothiazine diacetamide
4 (100 mg,
0.235 mmol) in a mixture of acetic acid (1 mL) and acetic anhydride
(2 mL) was added 30% aqueous hydrogen peroxide (0.144 mL,
1.41 mmol) at 0 ꢁC. The mixture was stirred at this temperature for
15 min, and then it was poured on ice-water (20 mL). The resulting
solid was collected by filtration to give 1 (75 mg, 70%). Diacetamide
1 had the same physical properties and spectral data as the one
prepared above from dinitrophenothiazine sulfoxide 3.
€
€
try, Institute for Chemistry, L. Eotvos University, Budapest, Hungary.
Melting points were taken on a Boetius micro-melting point ap-
paratus and were uncorrected. Mass spectra were recorded on an
Agilent-1200 Quadrupole LC/MS instrument using ESI method.
Suitable single crystals for X-ray crystallographic studies were
obtained from the almost saturated solutions of phenothiazine
derivatives (1, 3 and 5) in appropriate solvents (listed below for
each compound), which were allowed to stand at rt in glass vials.
The following solvents were used: AcOH for 1 and 5, and MeOH for
4.3. N,N0-(3,7-Di-tert-butyl-5,5-dioxido-10H-phenothiazine-
1,9-diyl)dibenzamide (2)
To a vigorously stirred solution of diaminophenothiazine sul-
fone 6 (0.5 g, 0.860 mmol) in pyridine (5 mL) was added benzoyl
chloride (413 mg, 2.94 mmol) at 0 ꢁC under Ar. Stirring was con-
tinued for 30 min, then the reaction mixture was poured onto ice-
water (50 mL), and the pH was adjusted to 4 using 30% aqueous
hydrochloric acid. The white solid was filtered off, and triturated
with MeOH to give 2 as white crystals (358 mg, 46%).
3. X-ray intensity data were collected on a Rigaku R-Axis Rapid
ꢁ
diffractometer with Mo K
a
radiation (
l
¼0.71075 A) at 123(2) K (1),
103(2) K (3) and 295(2) K (5). Numerical absorption corrections
were applied for all three data sets. A summary of crystal data and
structure refinement is given in Table S1 (see Supplementary data).
UVevis spectra were taken on a Unicam UV4-100 spectropho-
tometer. Quartz cuvettes with path length of 1 cm were used. Tet-
rabutylammonium salts of anions were purchased from
SigmaeAldrich Corporation. The stability constants of complexes
were determined by global nonlinear regression analysis using
SPECFIT/32Ô program. The pKa value of protonated triethylamine
in MeCN (18.82) was taken from the literature.34
Mp 334e335 ꢁC (MeOH); Rf 0.75 (silica gel TLC, MeOH/CH2Cl2
1:20); IR (KBr) nmax 3419, 3285, 3058, 2963, 2907, 2871, 1658, 1641,
1610, 1580, 1525, 1489, 1396, 1365, 1290, 1238, 1186, 1142, 1097, 877,
729, 715, 558, 550 cmꢀ1 1H NMR (500 MHz, DMSO-d6)
; d 1.36 (s,
18H, t-Bu), 7.30 (t, J¼8 Hz, 4H, ArH), 7.53 (t, J¼8 Hz, 2H, ArH),
7.78e7.80 (m, 8H, ArH), 8.93 (s, 1H, NH), 10.44 (s, 2H, NH); 13C NMR
(125 MHz, DMSO-d6)
d 30.85, 34.46, 115.58, 121.76, 125.84, 127.77,
128.09, 128.89, 131.42, 131.69, 133.15, 144.44, 166.34; MS calcd for
C34H35N3O4S: 581.2. Found (MꢀH)ꢀ: 580.2. Anal. Calcd for
C34H35N3O4S: C, 70.20; H, 6.06; N, 7.22; S, 5.51. Found: C, 69.93; H,
6.03; N, 7.15; S, 5.71.
4.2. N,N0-(3,7-Di-tert-butyl-5,5-dioxido-10H-phenothiazine-
1,9-diyl)diacetamide (1)
4.2.1. Starting
from
dinitrophenothiazine
sulfone
5. Dinitrophenothiazine sulfone 5 (10 g, 23.1 mmol) and acetic
anhydride (8.72 mL, 92.3 mmol) were dissolved in acetic acid
(350 mL) and hydrogenated in the presence of Pd/C catalyst (2 g,
palladium/charcoal; activated, 10% Pd) at 60 ꢁC. After the reaction
4.4. 3,7-Di-tert-butyl-1,9-dinitro-10H-phenothiazine 5-oxide (3)
4.4.1. Starting from di-tert-butylphenothiazine 7. To a vigorously
stirred solution of di-tert-butylphenothiazine 7 (40 g, 128.4 mmol)

7068
A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
in CH2Cl2 (400 mL) was added dropwise a freshly prepared ice-cold
mixture of fuming nitric acid (16.8 mL, 404.5 mmol) and acetic
anhydride (36.4 mL, 404.5 mmol) in CH2Cl2 (200 mL) under Ar
at ꢀ20 ꢁC. The reaction mixture was stirred at this temperature for
10 min then at rt for 2 h. The solvent was removed, the yellow solid
was triturated with water, filtered, and recrystallized from toluene
to give 3 (34.8 g, 65%) as yellow crystals.
4.7. 3,7-Di-tert-butyl-10H-phenothiazine-1,9-diamine 5,5-
dioxide (6)
4.7.1. Startingfrom dinitrophenothiazinesulfone 5. Dinitrophenothiazine
sulfone 5 (10 g, 23.1 mmol) was dissolved in 95% aqueous acetic acid
(350 mL) and hydrogenated in the presence of Pd/C catalyst (2 g, pal-
ladium/charcoal; activated, 10% Pd) at 60 ꢁC. After the reaction was
completed, the catalyst was filtered off, and the solution was concen-
trated to one-third of its original volume. The precipitated solid was
collected by filtration to give 6 (5.80 g, 67%) as a white solid.
Mp 217e219 ꢁC (toluene); Rf 0.26 (silica gel TLC, EtOAc/hexane
1:3); IR (KBr) nmax 3276, 3096, 2962, 2948, 2871, 1609, 1583, 1562,
1534, 1487, 1410, 1367, 1344, 1294, 1279, 1266, 1233, 1207, 1148,
1106, 1044, 930, 901, 878, 765, 709, 627, 438 cmꢀ1
;
1H NMR
Mp 279e281 ꢁC (AcOH); Rf 0.45 (silica gel TLC, MeOH/CH2Cl2
1:20); IR (KBr) nmax 3405, 3336, 3270, 2965, 2906, 2870, 1704, 1644,
1605, 1582, 1518, 1466, 1421, 1368, 1301, 1263, 1194, 1114, 1097, 983,
(500 MHz, CDCl3)
d
1.45 (s, 18H, t-Bu), 8.33 (s, 2H, ArH), 8.73 (s, 2H,
31.22, 35.21,
ArH), 13.65 (s, 1H, NH); 13C NMR (125 MHz, CDCl3)
d
125.55, 128.35, 129.29, 135.28, 136.02, 146.73. Anal. Calcd for
C20H23N3O5S: C, 57.54; H, 5.55; N, 10.07; S, 7.68. Found: C, 57.56; H,
5.42; N, 9.92; S, 7.69.
901, 877, 845, 779, 731, 704, 626, 569, 544, 498 cmꢀ1 1H NMR
;
(300 MHz, DMSO-d6)
2H, ArH), 7.08 (s, 2H, ArH), 8.03 (br s, 1H, NH); 13C NMR (75.5 MHz,
DMSO-d6) 31.15, 34.28, 105.06, 114.72, 120.70, 124.33, 136.44,
d 1.27 (s,18H, t-Bu), 5.65 (br s, 4H, NH), 7.07 (s,
d
4.4.2. Starting
from
mononitrophenothiazine
sulfoxide
144.58. Anal. Calcd for C20H27N3O2S$H2O: C, 61.35; H, 7.47; N,10.73;
8. Dinitrophenothiazine sulfoxide 3 was prepared as described
above starting from mononitrophenothiazine sulfoxide 8 (0.5 g,
1.34 mmol), fuming nitric acid (169 mg, 2.68 mmol), acetic anhy-
dride (274 mg, 2.68 mmol) and CH2Cl2 (6 mL). Recrystallization
S, 8.19. Found: C, 61.18; H, 7.22; N, 10.44; S, 8.02.
4.7.2. Starting from 5,5-dioxidophenothiazine-1,9-diamide 1. A
mixture of diacetamide 1 (3 g, 6.56 mmol) and 20% aqueous
hydrochloric acid (150 mL) was stirred under Ar at reflux temper-
ature for 4 h. The reaction mixture was cooled to 0 ꢁC, and the solid
was filtered off to give 6$2HCl (2.58 g, 88%) as white crystals. Mp
264e267 ꢁC (H2O); IR (KBr) nmax 3424, 2962, 2909 (br), 2585, 1625,
1574, 1530, 1498, 1417, 1367, 1353, 1276, 1186, 1140, 1119, 1084, 726,
from toluene gave
3 (0.35 g, 63%) as yellow crystals. Dini-
trophenothiazine sulfoxide 3 was identical in every respect as the
one prepared above from di-tert-butylphenothiazine 7.
4.5. N,N0-(3,7-Di-tert-butyl-10H-phenothiazine-1,9-diyl)
diacetamide (4)
540, 498 cmꢀ1
7.44 (d, J¼1 Hz, 2H, ArH), 7.51 (d, J¼1 Hz, 2H, ArH), 8.66 (br s, 6H,
NH), 9.42 (br s, 1H, NH); 13C NMR (75.5 MHz, DMSO-d6)
30.86,
; d 1.30 (s, 18H, t-Bu),
1H NMR (500 MHz, DMSO-d6)
d
Phenothiazine diacetamide 4 was prepared as described above
34.35, 110.91, 120.42, 122.08, 126.94, 129.28; 145.01. Anal. Calcd for
C20H29Cl2N3O2S: C, 53.81; H, 6.55; N, 9.41; S, 7.18. Found: C, 53.71;
H, 6.62; N, 9.32; S, 7.19. The dihydrochloride salt (2 g, 4.48 mmol)
was suspended in water (50 mL) and the pH was adjusted to 8 with
NaHCO3. The crystals were filtered off, and washed with water to
give 6 as a white solid (1.64 g, 98%). This product was used without
further purification. Diaminophenothiazine sulfone 6 had the same
physical properties and spectral data as the one prepared above
from dinitrophenothiazine sulfone 5.
for
1 starting from dinitrophenothiazine sulfoxide 3 (10 g,
23.95 mmol), acetic anhydride (9.06 mL, 95.81 mmol), Pd/C catalyst
(0.2 g, palladium/charcoal; activated, 10% Pd) and acetic acid
(350 mL). After the reaction was completed, the catalyst was fil-
tered off, and the solvent was evaporated. The crude product was
triturated with toluene to give 4 (8.64 g, 85%) as a white solid.
Mp 306e308 ꢁC (toluene); Rf 0.34 (silica gel TLC, MeOH/CH2Cl2
1:20); IR (KBr) nmax 3364, 3244, 2962, 2868, 1658, 1577, 1533, 1478,
1416, 1372, 1363, 1304, 1283, 1257, 1234, 1203, 1029, 980, 869, 850,
770, 734, 634, 613, 551 cmꢀ1 1H NMR (500 MHz, DMSO-d6)
; d 1.21
4.8. 3,7-Di-tert-butyl-10H-phenothiazine (7)
(s, 18H, t-Bu), 2.08 (s, 6H, COMe), 6.91 (s, 2H, ArH), 6.94 (s, 2H, ArH),
7.10 (s, 1H, NH), 9.54 (s, 2H, NH); 13C NMR (75.5 MHz, DMSO-d6)
To a vigorously stirred suspension of phenothiazine (20 g,
100.4 mmol) and anhydrous AlCl3 (28.1 g, 210.8 mmol) in CH2Cl2
(200 mL) was added tert-butyl chloride (54.6 mL, 502 mmol) drop-
wise under Arat 0 ꢁC. Afteraddition of tert-butyl chloride the mixture
wasstirred atthesame temperaturefor5 min, thenitwaspoured into
water (2 L), and NaOAc (55 g, 670 mmol) was added. The phases were
shaken well, separated, and the aqueous phase was extracted with
CH2Cl2 (4ꢂ200 mL). The combined organic phase was dried over
MgSO4, filtered, and the solvent was removed. The crude product was
triturated with hexane to give 7 as an off-white solid (27.5 g, 85%).
Mp 204e206 ꢁC (hexane) [lit.32 mp: 193e195 ꢁC (ligroin)]; Rf 0.63
(silica gel TLC, EtOAc/hexane 1:5); IR (KBr) nmax 3359, 3055, 3022,
2960, 2901, 2864, 1610, 1587, 1498, 1483, 1398, 1375, 1361, 1299, 1274,
1275, 1202, 1152, 1119, 1075, 1026, 878, 843, 822, 815, 748, 722, 685,
d
23.06, 30.99, 33.80, 119.13, 120.72, 121.86, 123.99, 134.13, 144.30,
168.84. Anal. Calcd for C24H31N3O3S: C, 65.28; H, 7.08; N, 9.52; S,
7.26. Found: C, 65.16; H, 7.34; N, 9.37; S, 7.16.
4.6. 3,7-Di-tert-butyl-1,9-dinitro-10H-phenothiazine 5,5-
dioxide (5)
A
mixture of dinitrophenothiazine sulfoxide
3
(12 g,
28.74 mmol) and 30% aqueous hydrogen peroxide (17.6 mL,
172.5 mmol) in acetic acid (300 mL) was stirred vigorously at
reflux temperature for 2 h. After the reaction was completed, the
mixture was cooled down to rt, the crystals were filtered off, and
recrystallized from acetic acid to give 5 (9.55 g, 77%) as yellow
crystals.
610, 554, 446 cmꢀ1; 1H NMR (300 MHz, DMSO-d6)
6.62 (d, J¼8 Hz, 2H, ArH), 6.89 (s, 2H, ArH), 6.98 (d, J¼8 Hz, 2H, ArH),
8.38 (s, 1H, NH); 13C NMR (75.5 MHz, DMSO-d6)
31.06, 33.71, 113.91,
d 1.19 (s, 18H, t-Bu),
Mp 235e237 ꢁC (AcOH); Rf 0.70 (silica gel TLC, EtOAc/hexane
1:3); IR (KBr) nmax 3229, 3135, 3070, 2965, 2872, 1614, 1578, 1566,
1524, 1501, 1468, 1411, 1365, 1337, 1311, 1295, 1277, 1269, 1231, 1164,
d
115.93, 122.89, 124.08, 139.86, 144.01. Anal. Calcd for C20H25NS: C,
77.12; H, 8.09; N, 4.50; S,10.29. Found: C, 76.84; H, 7.83; N, 4.33; S,10.16.
1141, 1097, 927, 901, 885, 759, 567, 522, 421 cmꢀ1 1H NMR
;
(500 MHz, DMSO-d6)
d
1.40 (s, 18H, t-Bu), 8.39 (s, 2H, ArH); 8.64 (s,
30.42,
2H, ArH), 12.79 (s, 1H, NH); 13C NMR (125 MHz, DMSO-d6)
d
4.9. 3,7-Di-tert-butyl-1-nitro-10H-phenothiazine 5-oxide (8)
Mononitrophenothiazine sulfoxide 8 was prepared as described
34.86, 124.14, 136.30, 128.02, 131.15, 135.34, 145.91. Anal. Calcd for
C20H23N3O6S: C, 55.42; H, 5.35; N, 9.69; S, 7.40. Found: C, 55.14; H,
5.11; N, 9.46; S, 7.43.
above for
3 starting from di-tert-butylphenothiazine 7 (5 g,

A. Kormos et al. / Tetrahedron 68 (2012) 7063e7069
7069
16.05 mmol), fuming nitric acid (1.4 mL, 33.71 mmol), acetic an-
References and notes
hydride (3.2 mL, 33.71 mmol) and CH2Cl2 (60 mL). Recrystallization
from toluene gave 8 (3.65 g, 61%) as yellow crystals.
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