Akylations of 10H-2,7-diazaphenothiazine to alkyl-2,7-diazaphenothiazinium salts and 7-alkyl-2,7-diazapheno-thiazines

Article abstract of DOI:10.3987/COM-10-12007

Alkylations of 10H-2,7-diazaphenothiazine (1) with alkyl halides led to different products depending on the reaction conditions: 10-methyl derivative (2), 2,10-dimethyl-2,7-diazaphenothiazinium and 7,10-dimethyl-2,7- diazaphenothiazinium iodides (3-4), 2,

Full text of DOI:10.3987/COM-10-12007

HETEROCYCLES, Vol. 81, No. 11, 2010
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HETEROCYCLES, Vol. 81, No. 11, 2010, pp. 2511 - 2522. © The Japan Institute of Heterocyclic Chemistry
Received, 5th July, 2010, Accepted, 7th September, 2010, Published online, 8th September, 2010
DOI: 10.3987/COM-10-12007
AKYLATIONS OF 10H-2,7-DIAZAPHENOTHIAZINE TO ALKYL-2,7-
DIAZAPHENOTHIAZINIUM SALTS AND 7-ALKYL-2,7-DIAZAPHENO-
#
THIAZINES
a
a,
b,c
Beata Morak-M!odawska, Krystian Pluta, * Kinga Suwi"ska,
and
a
Ma!gorzata Jele"
a
Department of Organic Chemistry, The Medical University of Silesia,
Jagiello!ska 4, 41-200 Sosnowiec, Poland. E-mail: pluta@sum.edu.pl
b
Institute of Physical Chemistry, Polish Academy of Sciences, Kasprzaka 44/52,
0
c
1-224 Warsaw, Poland
Faculty of Biology and Environmental Sciences, Cardinal Stefan Wyszynski
University, Wóycickiego 1/3, 01-938 Warsaw, Poland
Abstract – Alkylations of 10H-2,7-diazaphenothiazine (1) with alkyl halides led
to different products depending on the reaction conditions: 10-methyl derivative
(2), 2,10-dimethyl-2,7-diazaphenothiazinium and 7,10-dimethyl-2,7-diazapheno-
thiazinium iodides (3-4), 2,7-dialkyl-2,7-diazaphenothiazidiinium dihalides (5-8)
and 7-alkyl-2,7-diazaphenothiazines (9-12). The last compounds were the isomers
of recently published 10-alkyl-2,7-diazaphenothiazines. 2,7-Dialkyl-2,7-diazaphe-
nothiazidiinium dihalides (5) and (8) were transformed into 7-alkyl-2,7-diazaphe-
nothiazines (9) and (12) in basic conditions. The structures of the products were
1
determined on the basis of physical properties, H NMR (ROESY, COSY) and
MS spectra, and were confirmed by X-ray analysis of compounds (3-5).
INTRODUCTION
Phenothiazines are an important class of heterocyclic compounds because of significant biological
activities such as antipsychotic, antihistaminic, antitussive and antiemetic and interesting chemical
1
properties. Recent reports deal with anticancer, antiplasmid and antibacterial activities, reversal of
multidrug resistance (MDR) and potential treatment in Alzheimer’s, Creutzfeldt-Jakob and AIDS diseases
2
-10
of classical and new synthesized phenothiazines. A number of new phenothiazines have been obtained
by modifications of the parent phenothiazine structure by an introduction of a new substituent at the
thiazine nitrogen atom or at the benzene ring and by a substitution of one or two benzene rings with
9
-12
homoaromatic and heteroaromatic rings (most often azine rings).
1
3,14
In our previous papers
’,4’-e][1,4]thiazine, (named also as 10H-2,7-diazaphenothiazine (1)) and its 10-alkyl, aryl, heteroaryl
and dialkylaminoalkyl derivatives. The parent compound (1) and 10-methyl derivative (2) (less) showed
we described synthesis of new type of azaphenothiazine, 10H-dipyrido[3,4-b;-
3

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HETEROCYCLES, Vol. 81, No. 11, 2010
promising anticancer activity against lung cancers HOP-62 and HOP-92, colon cancers COLO 205 and
1
5
HCT-116, renal cancers RXF393 and A498, and leukemia HL-60(TB). Compounds (1) and (2) showed
1
6
also immunosuppressive activity.
As compound (1) possesses three nitrogen atoms, we studied possibilities of alkylations of two pyridine
nitrogen atoms to form 2,7-, 2,10- and 7,10-dialkyl-2,7-diazaphenothiazinium salts and 7-alkyl-2,7-
diazaphenothiazines.
RESULTS AND DISCUSSION
1
7-21
There is only a few reports
on the alkylations of other nitrogen atoms (=N- in azines) than the thiazine
ones (=NH) in azaphenothiazines. We found that when methylation of the parent compound (1) with
methyl iodide in basic conditions (DMF, NaH) at room temperature was prolonged (from 24 h to 72 h),
not only the product of the thiazine nitrogen atom methylation (10-methylderivative (2)) was obtained (in
1
9% yield) but first of all the products of methylation of both the thiazine and the pyridine nitrogen
atoms: 2,10-dimethyl-2,7-diazaphenothiazinium iodide (3) and 7,10-dimethyl-2,7-diazaphenothiazinium
iodide (4) in 51% yield (Scheme 1).
Me
N
2
4 h
N
N
S
2
H
N
DMF
N
+
MeI
N
NaH, rt
S
Me
Me
N
I
Me
N
1
N
7
2 h
Me
N
N
N
+
+
Me
N
N
N
S
S
S
2
I
4
3
Scheme 1
Compounds (3) and (4) turned out to be inseparable and what more they formed monocrystals containing
both the compounds in the ratio of 1:1. In order to confirm their structures, X-ray analysis was carried out
(
Figure 1).
When the alkylations with alkyl halides (methyl, ethyl and butyl iodides and benzyl chloride) in ethanol
without a base) at room or elevated temperature (depending on the alkylating agents), 2,7-dialkyl-2,7-
diazaphenothiazidiinium dichloride and diiodides (5–8, in 30-41% yield), and 7-alkyl-2,7-diazapheno-
(
R
(%)
R
Me
Et
(%)
H
N
H
N
R
N
5
6
Me 41
36 10
Bu 30 11
9
37
34
29
N
EtOH
N
N
+
RX
Et
+
N
N
4
8-120 h
N
S
R
S
R
S
7
Bu
1
2X
9-12
8 CH Ph 40 12 CH Ph 25
2
2
5
-8
X = I, Cl
Scheme 2

HETEROCYCLES, Vol. 81, No. 11, 2010
2513
thiazines (9–12, in 25-37% yield) were obtained (Scheme 2). In those conditions the NH group of the
thiazine ring was not alkylated but only the pyridine nitrogen atoms.
To confirm which nitrogen atoms were alkylated and to exclude the isomeric structure (13) (Figure 1),
X-ray analysis of disalt (5) was carried out (Figure 4).
Figure 1
7
-Methyl- and 7-benzyl-2,7-diazaphenothiazines (9) and (12) were obtained directly from salts (5) and (8)
in 68% and 70% yields in the action of aqueous sodium hydroxide, respectively.
H
N
R
N
N
NaOH
N
N
N
H O
2
R
S
R
S
2
X
5
9
R = Me, CH Ph X = I, Cl
2
Scheme 3
Physical and spectroscopic properties of 2,7-diazaphenothiazines
All alkylations were monitored by TLC analysis. The chromatograms of 2,7-diazaphenothiazinium
halides (3-8) and 7-alkyl-2,7-diazaphenothiazines (9-12) showed colored spots [(3-4) - bright yellow, (5-
6
) - bright orange, (7) - orange, (8) - intensive orange, (9-10) - intensive yellow, (11) - yellow and (12) -
canary yellow] which became more intensive during irradiation with UV lamp. When these chroma-
2
2
tograms were sprayed with a phenothiazine detection mixture (sulfuric acid-water-ethanol 1:1:8),
1
3
unlike to the chromatograms of 10-alkyl-2,7-diazaphenothiazines, the spot color disappeared for
compound (3-8) or became bright yellow (9-12). The R values of 7-alkyl-2,7-diazaphenothiazines (9–12)
were lower than analogous values of isomeric 10-alkyl-2,7-diazaphenothiazines. In contrary to
0-methyl-2,7-diazaphenothiazine (2) and 7-alkyl-2,7-diazaphenothiazines (9–12), salts (3–8) were
f
1
soluble in water. The Beilstein test of salts (3–8) showed the presence of the halogen atom and the
reactions with silver nitrate showed the chlorine and iodine atoms of anionic nature.
1
The H NMR spectra of the obtained azaphenothiazines were recorded in deuteriochloroform or dimethyl
6
sulphoxide-d and revealed two singlet signals and four doublet signals showing unsymmetrical structure
of the diazaphenothiazine system. Two singlet signals and two doublet signals were considered as !-
pyridinyl proton ones, two doublet signals as "-pyridinyl proton ones. The structure of 7-alkyl-2,7-
diazaphenothiazines (9–12) was based on the unquestionable assignment of the protons with the help of
1
1
homonuclear H- H ROESY and COSY experiments for 7-ethyl derivative (10). Four signals aromatic
proton signals at 6.58, 7.45, 8.02 and 8.09 ppm were doublets and two signals at 7.31 and 8.32 ppm were

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HETEROCYCLES, Vol. 81, No. 11, 2010
3 2
singlets. The ethyl group signals were found as a triplet at 1.58 ppm (CH ) and a quartet (CH ) at 4.21
ppm. ROESY experiment showed correlation of the CH and CH groups with each other and with the
2
3
singlet proton at 7.31 ppm and the doublet proton at 8.09 ppm, which were assigned as H6 and H8
protons, respectively (Figure 2). H8 proton correlated (ROESY, COSY) with the doublet proton at 7.45
ppm (J = 6.8 Hz) assigned as H9. The most upfield doublet proton at 6.58 ppm (being "-pyridinyl proton)
correlated (ROESY, COSY) with the doublet proton at 8.02 ppm (J = 5.1 Hz) and both protons were
assigned as H4 and H3, respectively.
a,b
H9
H6
H1
H8
N
S
a
N
a
N
H3
a,b H C
2
H4
H C
3
a
a,b
a
Figure 2. ROESY (a) and COSY (b) experiments in 7-ethyl-2,7-diazaphenothiazine (10).
All diazaphenothiazines and their salts (3–12) show promising potential antiinflammatory, anticancer,
2
3
antihistaminic, antiviral, cardiotonic and immunomodulating activities.
X-Ray study
2
8
Figure 3. Top: ORTEP drawings of monosalts (3) and (4) (molecule A and B, respectively); bottom:
mutual location of the two cations in the crystal, iodine anions and water molecules present in the crystal
are also shown.

HETEROCYCLES, Vol. 81, No. 11, 2010
2515
There are only two reports on the crystal structure of azaphenothiazinium salts (quinobenzothiazinium
2
4,25
and pyridoquinothiazinium chlorides) possessing different molecular conformations.
of compounds (3–5) confirmed their structures as 2,10- and 7,10-dimethyldiazaphenothiazinium iodides
monosalts, Figure 3) and 2,7-dimethyldiazaphenothiazidiinium diiodide (disalt, Figure 4).
The X-ray study
(
As was mentioned above, monosalts (3) and (4) form inseparable mixture and both tricyclic systems are
arranged alternatively in the molecular unit. Both compounds are folded along the N"""S axis. The folding
angles between the planes of the two halves of the thiazine ring (i. e. S1/C3/C4/N3 and S1/C13/C14/N3)
o
are 143.2(3) and 144.9(4) for compounds (3) and (4), respectively. Similarly, the angle between the
o
pyridine ring planes are 147.6(2) and 149.7(2) , respectively. The central thiazine ring is in the boat
conformation with the methyl group in equatorial location with the C18–N3"""S1 angle of 170.2(2) and
o
1
67.1(2) for compounds (3) and (4), respectively. The methyl groups of the external rings are coplanar
with the pyridine rings with the torsion angles C13–C12–N2–C17 and C15–C16–N2–C17 of 179.3(7) and
o
o
-
178.2(7) for compound (3), and 179.2(7) and 180.0(7) for compound (4). Whereas the C–S–C angle is
o
o
similar in both compounds (97.7(3) and 97.6(3) ), the C–N3–C angle is different (118.7(6) and 120.2(6) ).
Similarly the C–S bonds lengths are equal in compound (4) but different in compound (3). The N3–C
bonds lengths are different in both compounds (Table 1). The N3–CH
3
bond lengths are significantly
shorter than those N–CH bond lengths in the pyridine rings. These geometric parameters show
3
significant contribution of resonance structures (3’) and (4’) in the molecules (Scheme 4).
Table 1. The selected bond lengths [Å] in salts (3–5)
Bond
3
4
5
N
thiazine–CH
3
1.39(1)
1.37(1)
–
N–CH
3
1.473(9)
1.48(1)
1.485(7)
N
thiazine–C left/right
1.42(1)/ 1.39(1)
1.376(9)/1.413(9)
1.36 (2)/1.37(2)
1.79(2)/1.77(2)
S–C left/right
1.785(7)/ 1.757(1) 1.763(8)/1.759(7)
Me
N
Me
N
Me
N
Me
Me
N
Me
N
N
N
N
N
N
N
N
S
S
Me
S
Me
S
I
I
I
3
4
I
3`
4`
Scheme 4
The 1:1 mixture of (4) and (5) crystallizes with two water molecules. In the crystal the two types of
diazaphenothiazinium cations are stacked alternately in columns along crystallographic a axis is (Figure
5
). The distance between the r.m.s. planes of tricyclic systems of two neighbouring molecules in the stack

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HETEROCYCLES, Vol. 81, No. 11, 2010
is 3.61 Å. Between the columns along the b axis infinite 1D chains of hydrogen bonded water and iodide
species are located (Table 2).
In contrast to monosalts (3) and (4), disalt (5) is planar what is the result of an increase of the C–N–C and
o
C–S–C angles in central ring (123.53(6) and 100.98(6) , respectively) in comparison to the values
mentioned above for those compounds.
2
8
Figure 4. Top: ORTEP drawing of disalt (5); bottom: crystal packing, H-bonds between water
–
molecules, I anions and organic cations are shown with dotted lines.

HETEROCYCLES, Vol. 81, No. 11, 2010
2517
–
Figure 5. The packing of monosalts (3) and (4) in the crystal. H-bonds between water molecules and I
anions are shown with dotted lines.
3
The N–CH and N–C bond lengths are the same or similar but the C–S bonds are different (Table 1). The
molecule is located on crystallographic center of symmetry and, due to such location, is disordered
statistically 50:50 over two positions (Figure 4). Water molecules and iodide anions are hydrogen bonded
to form 1D infinite chains along crystallographic [101] direction. Additionally, the water molecules are
acceptors of hydrogen of diazaphenothiazinium cations just extending from 1D to 2D hydrogen bond
pattern (Table 2).
CONCLUSION
We report here synthesis of 2,7-, 2,10- and 7,10-dialkyl-2,7-diazaphenothiazinium monosalts and disalts
(3–8), and 7-alkyl-2,7-diazaphenothiazines (9–12) from 10H-2,7-diazaphenothiazine (1) depending on the
reaction conditions. The structures of products were determined using NOE and COSY experiments and
X-ray analysis of the selected compounds.

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HETEROCYCLES, Vol. 81, No. 11, 2010
Table 2. Hydrogen-bond geometry (Å, °)
D–H"""A
mixed crystal of (3) and (4)
O1W–H1WA"""I1 1.1(1)
D–H
H"""A
D"""A
D–H"""A
2.4(2)
2.6(2)
2.7(1)
2.7(1)
3.518(9)
3.63(1)
171(11)
170(11)
164(10)
164(11)
i
O1W–H1WB"""I2
O2W–H2WB"""I1
O2W–H2WA"""I2
crystal of (5)
1.0(1)
1.0(1)
0.8(1)
3.668(8)
3.506(7)
N2–H2A"""O1W
O1W–H1WA"""I1
0.88
1.87
2.74(1)
3.398(8)
3.375(8)
177
0.95(1)
0.95(1)
2.46(2)
2.45(3)
170(10)
164(10)
ii
O1W–H1WB"""I1
Symmetry codes: (i) #x#1/2, y#1/2, #z+1/2; (ii) x+1/2, #y+1/2, z+1/2
EXPERIMENTAL
Melting points were determined in open capillary tubes on a Boetius melting point apparatus and are
1
uncorrected. The H NMR spectra were recorded on a Varian Unity-Inova-300 and a Bruker DRX
spectrometers at 300 and 500 MHz in deuteriochloroform and dimethyl sulphoxide-d
6
with
tetramethylsilane as the internal standard. Fast Atom Bombardment mass spectra (FAB MS) were run in
glycerol on a Finnigan MAT 95 spectrometer at 70 eV. The thin layer chromatography was performed on
silica gel 60 F254 (Merck 1.05735) with CHCl
neutral (type E) (Merck 1.05581) with CHCl -EtOH (10:1 v/v) as eluents.
Synthesis of 10-methyl-2,7-diazaphenothiazine (2), 2,10-dimethyl-2,7-diazaphenothiazinium and
,10-dimethyl-2,7-diazaphenothiazinium iodides (3) and (4)
3
-EtOH (5:1 and 10:1 v/v) and on aluminum oxide 60 F254
3
7
To a stirred solution of 10H-2,7-diazaphenothiazine (1) (100 mg, 0.5 mmol) in dry DMF (5 mL) NaH (12
mg, 0.5 mmol, washed out with hexane) was added. The reaction mixture was stirred at rt for 1 h, methyl
iodide (0.39 mL, 6 mmol) was added in 3 portions and the stirring was continued for 72 h. The solvent
3
was distilled off in vaccuo, the residue was dissolved in CHCl and was purified by column
chromatography (aluminum oxide, CHCl -EtOH 5:1) to give:
3
1
3
1
2
. 10-Methyl-2,7-diazaphenothiazine (2) (20 mg. 19%); mp 56-57 °C (EtOH) (lit., mp 56-57 °C).
. 2,10-Dimethyl-2,7-diazaphenothiazinium iodide (3) and 7,10-dimethyl-2,7-diazaphenothiazinium
1
iodide (4) (a mixture 1:1, 90 mg, 51%). H NMR (DMSO-d ) #: 3.09 (s, 3H, CH ), 3.49 (s, 3H, CH ),
6
3
3
3
.98 (s, 3H, CH
Hz, 1H), 7.83 (d, J = 6.0 Hz, 1H), 8.21 (s, 1H,), 8.27 (d, J = 5.4 Hz, 1H), 8.32 (s, 1H), 8.33 (s, 1H), 8.36
d, J = 5.4 Hz, 1H), 8.42 (d, J = 6.0 Hz, 1H), 8.46 (s, 1H), 8.48 (d, J= 6.6 Hz, 1H). FAB MS m/z: 231
3 3
), 4.16 (s, 3H, CH ), 7.03 (d, J = 5.4 Hz, 1H), 7.31 (d, J = 6,6 Hz, 1H), 7.32 (d, J = 5.4
(

HETEROCYCLES, Vol. 81, No. 11, 2010
2519
(
M+1–I, 30), 230 (M+1–HI, 100), 216 (M+1–CH
3
I, 12). Anal. Calcd for C12
H12IN
3
S: C, 40.35; H, 3.39;
N, 11.76. Found C, 40.12; H, 3.21; N, 11.51.
Synthesis of 2,7-dimethyl-2,7-diazaphenothiazidiinium diiodide (5) and 7-methyl-2,7-diazapheno-
thiazine (9)
To a stirred solution of 10H-2,7-diazaphenothiazine (1) (100 mg, 0.5 mmol) in dry EtOH (5 mL) at rt,
methyl iodide (0.09 mL, 1.5 mmol) was added and the stirring was continued for 48 h. The resulted solid
was filtered off to give 2,7-dimethyl-2,7-diazaphenothiazidiinium diiodide (5) (100 mg, 41%), mp 249-
1
2
50 °C (EtOH). H NMR (DMSO-d
6
) #: 3.86 (s, 3H, CH
3
), 4.06 (s, 3H, CH
3
), 6.78 (d, J = 6.5 Hz, 1H, H4
or H9), 7.68 (d, J = 6.5 Hz, 1H, H4 or H9), 7.70 (s, 1H, H1 or H6), 8.15 (d, J = 6.5 Hz, 1H, H3 or H8),
8
2
.29 (d, J = 6.5 Hz, 1H, H3 or H8), 8.31 (s, 1H, H1 or H6), 11.02 (s, 1H, NH). FAB MS m/z: 230 (M+1–
HI, 100), 216 (M+1–HI and CH I, 24). Anal. Calcd for C12 S: C, 29.71; H, 2.70; N, 8.66. Found
3
13 2 3
H I N
C, 29.47; H, 2.60; N, 8.52.
3
The filtrate was concentrated and purified by column chromatography (aluminum oxide, CHCl -EtOH
1
5
:1) to give 7-methyl-2,7-diazaphenothiazine (9) (40 mg, 37%), mp 69-70 °C (EtOH). H NMR (CDCl
3
)
3
#: 3.89 (s, 3H, CH ), 6.59 (d, J = 4.2 Hz, 1H, H4), 7.12 (s, 1H, H6 ), 7.46 (d, J = 6.1 Hz, 1H, H9), 7.71 (d,
J = 4.2 Hz, 1H, H3), 8.03 (d, J = 6.1 Hz, 1H, H8), 8.37 (s, 1H, H1). EI MS m/z: 215 (M, 100), 200 (M–
CH , 52). Anal. Calcd for C11 S: C, 61.37; H, 4.21; N, 19.52. Found C, 61.22; H, 4.14; N, 19.38.
3
9 3
H N
Synthesis of 2,7-diethyl-2,7-diazaphenothiazidiinium diiodide (6) and 7-ethyl-2,7-diazapheno-
thiazine (10)
To a stirred solution of 10H-2,7-diazaphenothiazine (1) (100 mg, 0.5 mmol) in dry EtOH (5 mL) at rt,
o
ethyl iodide (0.24 mL, 3 mmol) was added and the stirring was continued at 45 C for 120 h. The resulted
solid was filtered off to give 2,7-diethyl-2,7-diazaphenothiazidiinium diiodide (6) (69 mg, 36%), mp 218-
1
2
19 °C (EtOH). H NMR (DMSO-d
6
) #: 1.41 (t, J = 7.2 Hz, 3H, CH
), 4.56 (q, J = 7.2 Hz, 2H, CH ), 6.80 (d, J = 6.5 Hz, 1H, H4 or H9), 7.64 (d, J =
.5 Hz, 1H, H4 or H9), 7.71 (s, 1H, H1 or H6), 8.15 (d, J = 6.5 Hz, 1H, H3 or H8), 8.25 (d, J = 6.5 Hz 1H,
3 3
), 1.53 (t, J = 7.2 Hz, 3H, CH ), 4.21
(
q, J = 7.2 Hz, 2H, CH
2
2
6
H3 or H8), 8.30 (s, 1H, H1 or H6), 10.02 (s, 1H, NH). FAB MS m/z: 258 (M+1–2HI, 10), 230 (M+1–HI
and C I, 19) 185 (2gly+1, 100). Anal. Calcd for C14 S: C, 32.77; H, 3.34; N, 8.19. Found C,
2.56; H, 3.23; N, 8.01.
2
H
5
17 2 3
H I N
3
3
The filtrate was concentrated and purified by column chromatography (aluminum oxide, CHCl -EtOH
1
5
:1) to give 7-ethyl-2,7-diazaphenothiazine (10) (38 mg, 34%); an oil. H NMR (CDCl
3
) #: 1.58 (t, J =
7
.8 Hz, 3H, CH
6.8 Hz 1H, H9), 8.02 (d, J = 5.1 Hz, 1H, H3), 8.09 (d, J = 6.8 Hz 1H, H8), 8.32 (s, 1H, H1). FAB MS
m/z: 230 (M+1, 100), 200 (M–C H , 14). Anal. Calcd for C H N S: C, 62.86; H, 4.84; N, 18.33. Found
3 2
), 4.21 (q, J = 7.8 Hz, 2H, CH ), 6.58 (d, J = 5.1 Hz, 1H, H4), 7.31 (s, 1H, H6), 7.45 (d, J
=
2
5
12 11
3
C, 62.69; H, 4.72; N, 18.13.
Synthesis of 2,7-dibutyl-2,7-diazaphenothiazidiinium diiodide (7) and 7-butyl-2,7-diazapheno-
thiazine (11)

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HETEROCYCLES, Vol. 81, No. 11, 2010
To a stirred solution of 10H-2,7-diazaphenothiazine (1) (100 mg, 0.5 mmol) in dry EtOH (5 mL) at rt,
butyl iodide (0.18 mL, 1.6 mmol) was added and the reaction mixture was refluxed for 24 h. The solvent
was distilled off, the residue was dissolved in a mixture CHCl
3
-EtOH (1:1) and purified by column
chromatography (aluminum oxide, CHCl -EtOH 1:1) to give:
3
1
1
. 2,7-Dibutyl-2,7-diazaphenothiazidiinium diiodide (7) (80 mg, 30%), mp 210-212 °C (EtOH). H NMR
(DMSO-d
6
) #: 0.89 (m, 6$, 2C$
3
2 2
), 1.28 (m, 4H, 2CH ), 1.76 (m, 4H, 2CH ), 4.12 (t, 2H, J = 7.0 Hz,
NCH
2
), 4.32 (t, 2H, J = 7.0 Hz, NCH
2
), 6.81 (d, 1H, J = 6.0 Hz, H4 or H9), 7.73 (d, 1H, J = 6.0 Hz, H4
or H9), 7.75 (s, 1H, H1 or H6), 8.25 (d, 1H, J = 6.0 Hz, H3 or H8), 8.38 (d, 1H, J = 6.0 Hz, H3 or H8),
.39 (s, 1H, H1 or H6), 11.01 broad s, 1H, NH).
FAB MS m/z: 314 (M+1–2HI, 100), 258 (M+1–HI and C
8
4
H
9
25 2 3
I, 88). Anal. Calcd for C18H I N S: C,
3
2
#
6
7
7.98; H, 4.43; N, 7.38. Found C, 37.75; H, 4.33; N, 7.29.
1
. 7-Butyl-2,7-diazaphenothiazine (11) (20 mg, 29%), mp 62-63 °C (EtOH). H NMR (CDCl
3
)
: #: 0.97 (t, J = 6.8 Hz, 3H, CH ), 1.33 (m, 2H, CH ), 1.71 (m, 2H, CH ), 3.68 (t, J = 6.8 Hz, 2H, NCH ),
3
2
2
2
.44 (d, J = 4.9 Hz, 1H, H4), 6.48 (d, J = 6.0 Hz, 1H, H9), 6.61 (s, 1H, H6), 7.13 (d, J = 4.9 Hz, 1H, H3),
.85 (d, J = 6.0 Hz, 1H, H8), 7.98 (s, 1H, H1). EI MS m/z: 257 (M, 100), 201 (M–C , 74). Anal. Calcd
S: C, 65.34; H, 5.87; N, 16.33. Found C, 65.13; H, 5.71; N, 16.16.
4
H
8
15 3
for C14H N
Synthesis of 2,7-dibenzyl-2,7-diazaphenothiazidiinium dichloride (8) and 7-benzyl-2,7-diazapheno-
thiazine (12)
To a stirred solution of 10H-2,7-diazaphenothiazine (1) (100 mg, 0.5 mmol) in dry EtOH (5 mL) at rt,
benzyl chloride (0.15 mL, 1.5 mmol) was added and the reaction mixture was refluxed for 48 h. After
cooling the resulted solid was filtered off to give 2,7-dibenzyl-2,7-diazaphenothiazidiinium dichloride (8)
1
(
90 mg, 40%), mp 211-212 °C (EtOH). H NMR (DMSO-d
6
2 2
) #: 5.32 (s, 2H, CH ), 5.56 (s, 2H, CH ),
6
.87 (d, J = 5.0 Hz, 1H, H4 or H9), 7.42-7.45 (m, 10H, 2C
6
H
5
), 7.67 (d, J = 5.0 Hz, 1H, H4 or H9), 7.95
(
s, 1H, H1 or H6), 8.32 (d, J = 5.0 Hz, 1H, H3 or H8), 8.45 (s, 1H, H1 or H6), 8.49 (d, J = 5.0 Hz, 1H, H3
or H8), 11.08 (s, 1H, NH). FAB MS m/z: 382 (M+1–2HCl, 68), 292 (M+1–HCl and C CH Cl, 42),
S: C, 63.43; H, 4.66; N, 9.25. Found C, 63.22; H, 4.57; N,
6
H
5
2
1
85 (2gly+1, 100). Anal. Calcd for C24
.02.
2 3
H21Cl N
9
3
The filtrate was concentrated and purified by column chromatography (aluminum oxide, CHCl -EtOH
1
1
0:1) to give 7-benzyl-2,7-diazaphenothiazine (12) (37 mg, 37%); 59-61 °C (EtOH). H NMR (CDCl
3
)
#
: 5.28 (s, 2H, CH
), 7.47 (d, J = 6.1 Hz, 1H, H9), 8.01 (m, 2H, H3 and H8), 8.35 (s, 1H, H1). FAB MS m/z: 292 (M+1,
00), 201 (M+1–CH C H , 28). Anal. Calcd for C H N S: C, 70.08; H, 4.50; N, 14.42. Found C, 69.88;
2 6 2
), 6.58 (d, J = 5.0 Hz, 1H, H4), 7.22 (s, 1H, H6), 7.33 (m, 2H, C H ), 7.45 (m, 2H,
6 3
C H
1
2
6
5
17 13
3
H, 4.32; N, 14.23.
Synthesis of 7-alkyl-2,7-diazaphenothiazines (9) and (12) from 2,7-dialkyl-2,7-diazaphenothiazi-
diinium dihalides (5) and (8)
To a solution of 2,7-dialkyl-2,7-diazaphenothiazidiinium dihalides (5) or (8) (0.2 mmol) in water (2 mL).

HETEROCYCLES, Vol. 81, No. 11, 2010
2521
1
5% aqueous NaOH solution (0.1 mL) was added. The solution became dark red and turbid. After 0.5 h
the solution was extracted with CHCl (3 x 3 mL). The extracts were dried with anhydrous sodium sulfate
and evaporated in vaccuo. The obtained residue was purified by column chromatography (aluminum
oxide, CHCl -EtOH 10:1) to give 7-methyl-2,7-diazaphenothiazine (9) (30 mg, 68%) or 7-benzyl-2,7-
3
3
diazaphenothiazine (12) (41 mg, 70%).
X-Ray analysis
Data for 2,7-diazaphenothiazinium salts (3), (4) and (5) were collected on a KappaApexII difractometer
with graphite monochromated MoK! radiation (" = 0.71073 Å). The structures were solved by direct
2
6
2
methods (SHELXS-97) and refined by full-matrix least-squares minimization based on all unique F
2
7
(SHELXL-97-2).
A. The crystals of a 1:1 mixture of compounds (3) and (4) were grown from EtOH-H
2
O (5:1) solution.
+
–
Crystal data: [C H N S] "I "H O, M = 375.23, monoclinic, a = 7.0775(2), b = 20.3626(8), c =
1
2
12
3
2
r
3
#1
1
8.9590(7) Å, ! = 95.111(2)°, space group P2
1
/n, V = 2721.4(2) Å , Z = 8, µ = 2.50 mm . 17319
reflections were collected which 5480 were independent and 4424 reflections with I > 2#(I) (Rint = 0.099).
2
2
2
the structure was refined to R[F > 2#(F )] = 0.066 and wR(F ) = 0.133. Absorption correction: multi-
2
9
scan from symmetry-related measurements Sortav (Blessing 1995) (Tmin = 0.523, Tmax = 0.785).
B. The crystals of compound (5) were grown from EtOH-H O (5:1) solution.
= 503.13, monoclinic, a = 6.3362(3), b = 14.9233(6), c =
2
2
+
–
Crystal data: [C12
.7638(4) Å, ! = 98.784(2)°, space group P2
were collected which 2377 were independent and 1982 reflections with I > 2#(I) (Rint = 0.054). The
13 3 2 r
H N S] "2I "H O, M
3
#1
8
1
/n, V = 818.96(6) Å , Z = 2, µ = 3.96 mm . 6037 reflections
2
2
2
structure was refined to R[F > 2#(F )] = 0.047 and wR(F ) = 0.092. Absorption correction: part of the
2
7
2
refinement model ($F) SHELX97-2 I/# threshold for reflections = 5.0 $(U)/" = 0.0, highest even order
spherical harmonic = 8, highest odd order spherical harmonic = 5 (Tmin = 0.315, Tmax = 0.749).
For both structures H-atoms were included in geometric positions and refined as ‘riding’ atoms (H-atoms
of water molecules were located in a difference Fourier map of the electron density and included in the
refinement, and their positional parameters were refined) with isotropic thermal parameters based upon
3 2
the corresponding bonding carbon atom (Uiso = 1.5Ueq for CH and H O and Uiso = 1.2Ueq for the
aromatic carbons).
ACKNOWLEDGMENT
The work is supported by the Medical University of Silesia (grant KNW-1-008/10).
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