On the microwave-assisted synthesis of acylphenothiazine derivatives - Experiment versus theory synergism

Article abstract of DOI:10.1139/V09-163

The microwave-assisted synthesis of a series of acylphenothiazine derivatives is described. 10H-Phenothiazine-3-carbaldehyde derivatives were obtained in moderate yields by the Duff formylation reaction, and 10-acetyl-phenothiazine derivatives were obtained in excellent yields by acetylating phenothiazine derivatives with acetic anhydride. A theoretical explanation for the chemoselectivity and regioselectivity of these acylation reactions applied to phenothiazine substrates was attempted by molecular-modeling analyses based on molecular mechanics, and semi-empirical and DFT calculations.

Full text of DOI:10.1139/V09-163

4
2
On the microwave-assisted synthesis of
acylphenothiazine derivatives — Experiment
versus theory synergism
Luiza Gaina, Dan Porumb, Ioan Silaghi-Dumitrescu, Castelia Cristea, and
Luminita Silaghi-Dumitrescu
Abstract: The microwave-assisted synthesis of a series of acylphenothiazine derivatives is described. 10H-Phenothiazine-
3
-carbaldehyde derivatives were obtained in moderate yields by the Duff formylation reaction, and 10-acetyl-phenothiazine
derivatives were obtained in excellent yields by acetylating phenothiazine derivatives with acetic anhydride. A theoretical
explanation for the chemoselectivity and regioselectivity of these acylation reactions applied to phenothiazine substrates
was attempted by molecular-modeling analyses based on molecular mechanics, and semi-empirical and DFT calculations.
Key words: phenothiazine, microwave-assisted organic synthesis (MAOS), Duff formylation, acetylation, DFT calculations,
electrostatic potential.
R e´ sum e´ : On d e´ crit la synth e` se assist e´ e par des microondes d’une s e´ rie de d e´ riv e´ s de l’acylph e´ nothiazine. On a obtenu le
1
0H-ph e´ nothiazine-3-carbald e´ hyde avec des rendements mod e´ r e´ s en faisant appel a` une r e´ action de formylation de Duff
alors que les d e´ riv e´ s de la 10-ac e´ tylph e´ nothiazine ont e´ t e´ obtenus avec d’excellents rendements par ac e´ tylation des d e´ riv e´ s
de la ph e´ nothiazine a` l’aide d’anhydride ac e´ tique. On a essay e´ de trouver une explication th e´ orique de la chimios e´ lectivit e´
et de la r e´ gios e´ lectivit e´ de ces r e´ actions d’acylation appliqu e´ es a` des substrats ph e´ nothiazines en faisant appel a` des analy-
ses de modelages mol e´ culaires bas e´ s sur des calculs de m e´ canique mol e´ culaire, semi-empiriques ou des calculs bas e´ s sur
la th e´ orie de la th e´ orie de la fonctionnelle de densit e´ .
Mots-cl e´ s : ph e´ nothiazine, synth e` ses organiques assist e´ es par des microondes (SOAM), formylation de Duff, ac e´ tylation,
calculs bas e´ s sur la th e´ orie de la th e´ orie de la fonctionnelle de densit e´ (TFD), potentiel e´ lectrostatique.
[
Traduit par la R e´ daction]
Introduction
rivatives were obtained by microwave-assisted thiation of
diarylamines in reactions of neat reactants or adsorbed
The increased popularity of the microwave-assisted or-
ganic synthesis (MAOS) technique in chemical synthesis
on a laboratory scale is based on particularly efficient heat-
ing processes which afford shorter reaction times and offer
the possibility of rapid optimization of the reaction condi-
tions. An increasing number of published papers, several
books,1 and review articles show that almost all conven-
tionally heated reactions, including synthesis and function-
alization of heterocyclic compounds, were performed using
8,9
onto inorganic supports such as alumina and bentonite,
10
and in water as a solvent. Chalcones containing pheno-
thyazine units were succesfully synthesized by microwave-
assisted condensation of (hetero)aromatic carbonyl deriva-
11
tives.
One aim of this work was to optimize the microwave-as-
sisted reaction conditions, as an eco-friendly approach for
the synthesis of acyl-phenothiazine derivatives. These deriv-
atives might prove to be useful substrates in the formation
of coupled hetereocyclic systems, by forming new C=C
bonds in condensation reactions. Suitable substituted pheno-
thiazine derivatives are candidates for developing poten-
tially interesting organic solid-state properties (such as
unconventional physical, nonlinear optical, magnetic, and
(or) electrical properties), based on the well-known electron
donor effect of the phenothiazine nucleus characterized by
low and highly reversible first oxidation potential and a
,2
3
,4,5
6
7
this technique.
Since 1986, when Gedye and Giguere
carried out the first reported organic syntheses using sealed
vessels heated in domestic microwave ovens, several meth-
ods have been developed for the preparation of samples
(
with or without solvent) in both pressurized or open vessel
systems; meanwhile dedicated multimode or monomode
microwave reactors have been designed. Phenothiazine de-
Received 13 March 2009. Accepted 16 October 2009. Published
on the NRC Research Press Web site at canjchem.nrc.ca on
12
pronounced tendency to form stable cation-radicals. Fur-
thermore, when the 10H-phenothiazine unit appears unsub-
stituted at the heterocyclic nitrogen atom, the cation-radical
formed by single-electron oxidation may be involved in
1
8 December 2009.
1
L. Gaina, D. Porumb, I. Silaghi-Dumitrescu, C. Cristea, and
L. Silaghi-Dumitrescu. Babe s¸ -Bolyai University, Faculty of
Chemistry and Chemical Engineering, 11, Arany Janos Street,
protolytic equilibria as well, thus generating the isoelec-
13–15
tronic conjugate base, the neutral radical.
Potential new
4
00028 Cluj-Napoca, Romania.
materials may be obtained using such redox-active and pH-
sensitive heterocyclic building blocks.
1Corresponding author (e-mail: pdan@chem.ubbcluj.ro).
Can. J. Chem. 88: 42–49 (2010)
doi:10.1139/V09-163
Published by NRC Research Press

Gaina et al.
43
Scheme 1.
Experimental techniques
H
N
H
N
To ensure highly reproducible reaction conditions, the ex-
perimental technique employed for the microwave-assisted
syntheses of acylphenothiazine derivatives described below
is based on microwave power processing of materials using
a microwave instrument Synthos 3000; this system provides
multi-mode heating in sealed vessels equipped with built-in
magnetic stirrer, pressure sensors, and internal temperature
measurement. The instrument ensures cooling mechanisms,
online power, and temperature control using the feedback
from IR thermography. Software operation provides high-
precision reaction control.
(
H2C)6N4
AcOH
MW
R
CHO
R
S
S
1
R= -H
R= -CH3
2
R
N
R
N
(
H2C)6N4
AcOH
MW
S
S
CHO
3 R= -CH3
R= -CH2-(CH2)5
4
N
S
Results and discussion
fluoromethyl group attached in position 2 of the phenothia-
zine substrate does not reduce the reactivity for electrophilic
aromatic substitution in position 3, so that 3-formyl- and 7-
formyl-phenothiazine derivatives were obtained. When 2-
chlorophenothiazine was subjected to the Duff formylation
reaction, the two monoformyl derivatives 2-chloro-7-formyl-
phenothiazine (5a) and 2-chloro-3-formylphenothiazine (5b)
were obtained in 1.5:1 ratio.
The chemical reactivity of phenothiazine towards electro-
philic substitution was demonstrated in the preparation of
numerous examples of N- or C-substituted derivatives.
Chemical syntheses of acylphenothiazine derivatives were
previously performed under conventional heating techniques
which required long reaction times and usually generated
mixtures of constitutional isomers. Although phenothiazine
16
2-Trifluoromethyl-phenothiazine generated the 3,7-di-
formyl-2-trifluoromethylphenothiazine (6) as the main reac-
tion product, in moderate yields.
carbaldehydes were obtained by Vilsmeyer formylation
1
7
and Bergman formylation of N-alkyl-phenothiazine deriva-
tives, this method is inappropriate for the C-formylation of
The reaction conditions employed for these microwave-as-
sisted syntheses (reaction temperature, reaction time, and
ramp time to achieve the prescribed temperature) are shown
in Table 1. Temperature-controlled experiments in the tem-
perature range 150–190 8C show enhanced reactivity of un-
substituted phenothiazine as compared to substituted
derivatives. Similar reaction conditions (time, temperature)
were required for the formylation of alkyl-, 2-chloro-, and
2-trifluoromethyl-phenothiazine derivatives. Despite the al-
kyl chain length or its position in the substrate, mono
formyl-derivatives were isolated, even in the case of 1,6-bis-
1
0H-phenothiazine because of the formation of N-formyl-
phenothiazine derivatives in competitive reactions. We wish
to report here a direct and C-regioselective formylation of
0H-phenothiazine substrates, based on the Duff reaction,18
1
as the only reaction strategy generating good yields of 10H-
phenothiazin-3yl-carbaldehydes. Our promising results
obtained by the microwave-assisted Duff formylation of un-
substituted 10H-phenothiazine encouraged us to continue
to apply this mild formylation reaction to several other sub-
strates such as methyl-, halogeno-, and trifluoromethyl-10H-
phenothiazine.
1
1
(
phenothiazin-10yl)-hexane which contains two equivalent
Microwave-assisted synthesis of 10H-phenothiazine-3-
carbaldehyde derivatives
phenothiazine units. Good yields of diformyl-phenothiazine
derivative were obtained in the formylation of 2-trifluoro-
methyl-phenothiazine.
The regioselectivity of this reaction was experimentally
proved by the failure of the formylation reaction when 3,7-
dibromo-10-methylphenothiazine was subjected to a micro-
wave-assisted Duff formylation reaction.
The microwave-assisted synthesis of 3-formyl-10H-
phenothiazine derivatives was performed in the resonance
cavity of a Synthos 3000 instrument by multimode micro-
wave irradiation in pressurized systems (sealed quartz ves-
sels) using acetic acid, a polar solvent which ensures a
medium absorption efficiency and heating rate (tand =
The structure assignments of compounds 1–6 are sup-
ported by spectroscopic data. FTIR spectroscopy indicates
the stretching vibration of N–H bond in compounds 1, 2, 5,
1
9
0
.174, dielectric loss 3@ = 1.079).
-Formyl-10H-phenothiazine (1) was synthesized in
moderate yields by the microwave-assisted reaction of
0H-phenothiazine with urotropine in acetic acid solution.
3
–1
and 6, by the absorption band situated near 3300 cm . The
substitution in position 3 of the phenothiazine units was un-
ambiguously assigned according to the NMR spectra. The
coupling patterns of the aromatic protons observed for the
1
The same regioselectivity for substitution in position 3 of
the heterocyclic substrate was observed in the microwave-
assisted Duff formylation of some alkyl-substituted 10H-
phenothiazine derivatives such as 3-methyl-phenothiazine,
1
H NMR signals were assigned using the 2D homocorrela-
tion COSY–45 spectra for each of products 1–6. 13C NMR
spectra together with 2D NMR heterocorrelation spectra
HMQC and HMBC afforded the complete structural assign-
ments.
10-methyl-phenothiazine, and 1,6-bis-(phenothiazin-10-yl)-
hexane (Scheme 1).
The microwave-assisted Duff formylation reactions of
some 2-substituted phenothiazine derivatives were also per-
formed. As shown in Scheme 2, different carbaldehyde re-
gioisomers may be formed according to the influence
exerted by the substituent.
Microwave-assisted synthesis of acetyl-10H-
phenothiazine derivatives
Acetylation of 10H-phenothiazine derivatives using acetic
anhydride generates different N-acetyl-10H-phenothiazine
Electron-withdrawing substituents such as chlorine or tri-
Published by NRC Research Press

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4
Can. J. Chem. Vol. 88, 2010
Scheme 2.
H
N
H
N
H
N
H
N
X
(H2C)6N4
X
X
X
+
+
AcOH
MW
S
S
CHO OHC
S
OHC
S
CHO
X= -Cl, -CF3
5a X= -Cl
5b X= -Cl
6 X= -CF3
Table 1. Experimental conditions for the microwave-assisted Duff formylation reaction of phenothiazine
derivatives using a Synthos 3000 microwave installation (reaction temperature, reaction time, and ramp
time to achieve the prescribed temperature).
Product
1
Substrate
10H-Phenothiazine
T (8C)
120
Time/ramp (min)
30/10
80
Yield (%)
50
1
1
50
20
30
2
3
4
3-Methyl-10H-phenothiazine
150
5/4
60
20
20/4
60
10
60/2
10
20/10
80
5/4
99
30
50
50
45
1
1
70
90
10-Methyl-phenothiazine
140
1
1
70
80
1,6-Bis-(phenothiazin-10yl)-hexane
2-Chloro-10H-phenothiazine
170
00
2
5
5
6
a
b
150
170
150
65
5a/5b = 1.5:1
65
2-Trifluoromethyl-10H-phenothiazine
1
1
70
80
—
3,7-Dibromo-10H-phenothiazine
100
70
10/5
30
—
1
Scheme 3.
CO-CH3
N
H
N
X
X
Ac O
2
H PO
3
4
S
S
MW
7
8
9
X= -H
X= -Cl
X= -CF3
X= -H, -Cl, -CF3
CH3
N
CH3
N
CH3
N
Ac O
2
+
H PO
3
4
S
S
CO-CH3 H3C-OC
S
CO-CH3
MW
10
11
and C-acetyl-10H-phenothiazine regioisomers according to
the reaction conditions applied.
time was allowed, 3,7-diacetyl-10-methylphenothiazine (11)
was obtained in good yields.
2
0,21
Spectroscopic data support the structure assignment of
acetyl-derivatives 7–11. The recorded 300 MHz H NMR
spectra show the diagnostic appearance of a singlet signal
for the acetyl group protons situated at 2.5 . Complete struc-
tural assignment for the aromatic protons and carbon atoms
was performed by 2D NMR correlation spectra (COSY-45,
HMQC and HMBC).
The microwave-assisted acetylation of phenothiazine
substrates was found to be highly chemoselective; N-acetyl-
phenothiazine derivatives were obtained in almost quantita-
tive yields. Scheme 3 presents the reactions of phenothiazine
derivatives with acetic anhydride in the presence of catalytic
amounts of phosphoric acid.
1
In the microwave-assisted acetylation of 10-methyl-phe-
nothiazine, 3-acetyl-10-methylphenothiazine (10) was ob-
Molecular modeling
tained in excellent yields. Table
2 summarizes the
experimental conditions employed for the microwave-
assisted acetylation of phenothiazine derivatives.
As expected, the less-reactive substrate in the acetylation
reaction was N-methylphenothiazine. When longer reaction
The chemoselectivity and regioselectivity of these acyla-
tion reactions of the phenothiazine nucleus observed by ex-
perimental results were compared with theoretical data
generated by DFT calculations.
Published by NRC Research Press

Gaina et al.
45
Table 2. Experimental conditions for the microwave-assisted acetylation reaction of phenothiazine
derivatives using a Synthos 3000 microwave installation (reaction temperature, reaction time, and
ramp time to achieve the prescribed temperature).
Product
7
Substrate
10H-Phenothiazine
T (8C)
60
Time/ramp (min)
10/2
30
Yield (%)
98
7
0
8
9
2-Chloro-10H-phenothiazine
2-Trifluoromethyl-10H-phenothiazine
10-Methyl-phenothiazine
60
10/2
30
10/2
30
5/3
10
5/3
30
96
97
45
55
7
0
60
7
0
1
1
0
1
60
8
0
10-Methyl-phenothiazine
60
8
0
Table 3. Electrostatic atomic charges calculated in phenothiazine substrates and intermediates, candidates for aromatic electrophilic sub-
stitution.
Electrostatic atomic charge in positions:
Compound
2
3
7
8
10
1
1
1
3
2
2
2
2
3
7
0H-Phenothiazine
0-Methylphenothiazine
,6-Bis(phenothiazin-10-yl)-hexane
-Methyl-10H-phenothiazine
-Chloro-10H-phenothiazine
-Trifluoromethyl-10H-phenothiazine
-Chloro-3-formyl-10H-phenothiazine
-Chloro-7-formyl-10H-phenothiazine
-formyl-2-trifluoromethyl-10H-phenothiazine
-Formyl-2-trifluoromethyl-10H-phenothiazine
–0.038
–0.131
–0.111
–0.257
0.109
0.175
0.173
0.234
0.005
0.175
–0.226
–0.175
–0.189
0.365
–0.201
–0.299
–0.027
–0.297
–0.097
–0.358
–0.226
–0.175
–0.156
–0.121
–0.213
–0.193
–0.236
–0.013
–0.183
0.044
–0.038
–0.131
–0.150
–0.059
–0.051
–0.055
–0.031
–0.044
–0.056
–0.079
–0.661
–0.213
–0.512
–0.616
–0.638
–0.629
–0.618
–0.607
–0.596
–0.615
The minimum energy geometry of each phenothiazine de-
The electrostatic potential surfaces (–18 kcal/mol isoval-
rivative employed as a substrate in acylation reactions was
obtained starting with molecular mechanics optimization of
the conformers generated within the Confanal module of
Spartan’06,22 followed by semi-empirical (PM3) and 6–
ues) for relevant alkylphenothiazine substrates are also shown
in Fig. 1. In each case, it can be noticed that the region around
position 3 of the substrate exhibits a relatively high area of
negative electrostatic potential, thus supporting the availabil-
ity of this atom to electrophilic attack, in agreement with ex-
perimental data regarding the regioselective aromatic
electrophilic substitution performed by the soft electrophile
(see Schemes 1 and 2). Notable is the shape of the –18 kcal/
mol electrostatic potential surface for 1,6-bis(phenothiazin-
10-yl)-hexane (Fig. 1b) located only on one of the phenothia-
zine rings suggesting that only one of the rings is subjected to
a possible electrophilic attack. Indeed, experimental data
show that only a monocarbaldehyde 4 is formed under the ex-
perimental conditions within this work.
The formation of a mixture of carbaldehydes 5a and 5b in
a 1.5:1 ratio (Table 1) during the formylation of 2-chloro-
phenothiazine is understandable in view of the electrostatic
charges (Table 3) in positions 7 (–0.213) and 3 (–0.201).
The generated electrostatic potential surface (isovalue
–15 kcal/mol) for 2-chloro-10H-phenothiazine is shown in
Fig. 2b and may also suggest the slightly higher preference
for the formation of 5a. Moreover, once position 3 (or 7) is
substituted, no significant negative electrostatic potential is
noticed in position 7 or 3 (Fig. 2a or 2c). According to
Figs. 2a and 2c further electrophilic attack is suppressed
since no negative electrostatic potential in position 7 of 5a
2
3–25
3
1G(d) B3LYP DFT
calculations on all such obtained
conformers. The following discussion applies to the lowest
energy conformers.
Theoretical explanations for the regioselectivity of the
Duff formylation reaction and the chemoselectivity of the
acetylation reaction, respectively, applied to substituted phe-
nothiazine substrates may be formulated on the basis of the
electrophilic aromatic substitution reaction mechanism. The
+
+
soft electrophile H C=N < $ H C –N< generated by uro-
2
2
tropine during the Duff formylation reaction may selectively
attack heterocyclic carbon atoms in positions characterized
by high electron density, whereas the acylium ion H C–CO
+
3
generated by the acetic anhydride in acidic media is a hard
electrophile and it is preferentially attached to the heterocy-
clic nitrogen atom. Here, we adopt the electrostatic charges
derived from the electrostatic potential as an indicator of the
preferred reaction site on the ring. These atomic charges
given in Table 3 show the highest (negative) value on the
nitrogen atom (position 10 of the heterocyclic substrate),
followed by the values assigned to the carbon atoms in posi-
tions 3 and 7, for each phenothiazine substrate employed in
experimental acylation reactions.
Published by NRC Research Press

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Can. J. Chem. Vol. 88, 2010
Fig. 1. Generated electrostatic potential (grayish envelope denotes
negative electrostatic potential at isovalue –18 kcal/mol) for
Fig. 2. Generated electrostatic potential (grayish envelope denotes
negative electrostatic potential at isovalue –15 kcal/mol); (a) 2-
chloro-3-formyl-10H-phenothiazine (5b), (b) 2-chloro-10H-
phenothiazine, (c) 2-chloro-7-formyl-10H-phenothiazine (5a).
(
(
a) 10H-phenothiazine, (b) 1,6-bis(phenothiazin-10-yl)-hexane,
c) 10-methylphenothiazine, (d) 3-methyl-10H-phenothiazine.
Conclusions
The Duff formylation reaction of phenothiazine deriva-
tives appears for the moment as the only efficient alternative
for obtaining new 10H-phenothiazine-3-carbaldehyde deriva-
tives containing a free amino group able to participate in
protolytic equilibria, as well as in redox processes character-
istic for this heterocycle. The microwave-assisted Duff for-
mylation reaction of phenothiazine derivatives is
a
technique which gives satisfactory experimental results af-
fording good yields of 10H-phenothiazine-3-carbaldehyde
derivatives.
The microwave-assisted acetylation reaction produced
good to almost quantitative yields, in most of the experi-
ments performed using phenothiazine substrates. Compari-
son of microwave-assisted synthesis with the conventional
synthetic methods demonstrates advantages related to shorter
reaction times and higher regioselectivity.
The electrostatic potential surfaces generated on the basis
of 6–31G(d) B3LYP calculations support the preference for
electophilic attack and explain the regioselectivity of formy-
lation reactions.
(
Fig. 2a), or in position 3 of 5b (Fig. 2c) is displayed. Thus,
the formation of a 3,7-dicarbaldehyde derivative of 2-chloro-
0H-phenothiazine is not expected and the experimental
1
procedures applied to the formylation of 2-chlorophenothia-
zine confirmed the theoretical hypothesis by leading only to
monocarbaldehydes 5a and 5b.
In contrast, the experimental formation of 3,7-dicarbalde-
hyde (6) is supported by possible formylation of 2-trifluoro-
methyl-10H-phenothiazine-monocarbaldehyde intermediates.
Note in Fig. 3 that negative electrostatic potential surfaces
appear around the carbon atoms in position 7 of the 3-car-
baldehyde intermediate (Fig. 3c) and in position 3 of the 7-
carbaldehyde intermediate, respectively (Fig. 3b).
Experimental section
The reactions were performed using a microwave installa-
tion Synthos 3000. Reagents from Merck were used. TLC
was used to monitor the reaction progress (Merck silica gel
F 254 plates). NMR spectra were recorded using a 300 MHz
Brucker Avance NMR spectrometer. FTIR spectra were re-
corded using a Brucker Vector 22 FTIR spectrometer. Ele-
mental analysis was carried out on a Thermo FlashEA 1112
Series instrument. The lowest-energy conformers generated
Published by NRC Research Press

Gaina et al.
47
3
3
Fig. 3. The electrostatic potential surface (grayish envelope denotes
negative electrostatic potential at isovalue –10 kcal/mol); (a) 2-tri-
fluoromethyl-10H-phenothiazine, (b) 7-formyl-2-trifluoromethyl-
8 Hz, J = 7.6, 1H, H ), 6.70 (d, J = 7.6 Hz, 1H, H ), 6.75
7
4
1
3
13
(dd, J = 8 Hz, J = 2 Hz,1H, H9).
C NMR
(75.4MHz,CDCl , ppm) d: 113.88 (CH, C ), 113.93 (CH,
3
1
1
0H-phenothiazine, (c) 3-formyl-2-trifluoromethyl-10H-phenothia-
C ), 116.69 (C , C ), 115.77 (C , C ), 130.43 (CH,
9 quat 4a quat 5a
zine.
C ), 127.36 (CH, C ), 123.07 (CH, C ), 126.24 (CH, C ),
2 4 7 6
1
1
6
27.83 (CH, C ), 130.9 (C , C ), 139.57 (Cquat, C9a),
8 quat 3
47.12 (Cquat, C10a). Anal. calcd. for C H NOS (227.2): C
13
9
8.70, H 3.99, N 6.16; found: C 68.62, H 3.99, N 6.09.
7
-Methyl-10H-phenothiazine-3-carbaldehyde (2)
1
H NMR (300 MHz, CDCl , ppm) d: 2.22 (s, 3H), 6.54
3
3
3
(
d, J = 7.5 Hz, 1H, H ), 7.48 (d, J = 7.5 Hz 1H, H ), 7.44
1
2
(
s, 1H, H ), 6.78 (s, 1H, H ), 9.72 (s, 1H, CHO), 6.81 (d,
4 6
3
3
J = 7.7 Hz, 1H, H ), 6.44 (d, J = 7.7 Hz, 1H, H ), 6.04 (s,
8
9
1
4
H, NH). Anal. calcd. for C H NOS (241.3): C 69.68, H
.59, N 5.80; found: C 69.60, H 4.58, N 5.85.
14 11
1
0-Methyl-10H-phenothiazine-3-carbaldehyde (3)
Yellow precipitate recrystallized from toluene, mp
8
8 8C.1
6,27 1
H NMR (300 MHz, CDCl , ppm) d: 9.80 (s, 1H
3
4
3
CHO), 7.65 (dd, J = 2 Hz, J = 8.4 Hz, 1H H ), 7.59 (d,
J = 2 Hz, 1H, H ), 7.18 (td, J = 1.4 Hz, J = 8.4 Hz, 1H,
H ), 7.12 (dd, J = 1.4 Hz, J = 7.6 Hz, 1H, H ), 6.98 (t,
J = 7.6 Hz, J = 8.4, 1H, H ), 6.85 (d, J = 8.4 Hz, 1H,
2
4
4
3
4
4
3
8
6
3
3
3
7
3
13
H ), 6.84 (d, J = 8 Hz, 1H, H ), 3.42 (s, 3H). C NMR
1
9
(
75.4 MHz, CDCl , ppm) d: 35.84 (CH ), 113.72 (CH, C ),
14.78 (CH, C ), 131.16 (CH, C ), 123.98 (Cquat, C4a),
9 3
3 3 1
1
1
1
22.53(Cquat, C ), 130.48 (CH, C ), 127.96 (CH, C ),
5a
2
4
23.64 (CH, C ), 127.31 (CH, C ), 127.78 (CH, C ), 144.09
7
6
8
(
(
5
Cquat, C ), 151.10 (Cquat, C10a). Anal. calcd. for C H NOS
241.3): C 69.68, H 4.59, N 5.80; found: C 69.59, H 4.58, N
.87.
9a 14 11
1
3
0-(6-(10H-Phenothiazin-10-yl)hexyl)-10H-phenothiazine-
-carbaldehyde (4)
by using the MMFF force field implemented in Spartan’04
have been further fully optimized using the 6–31G(d)
B3LYP hybrid DFT method.
Yellow precipitate recrystallized from toluene, mp
98 8C.2 H NMR (300 MHz, CDCl3, ppm) d: 3.85 (t, 4H),
8 1
2
3–25
1.79 (m, 4H), 1.46 (m, 4H), 9.80 (s, 1H), 6.86 (m, 4H, H1,9),
6
(
.92 (td, 2H, H ), 6.97 (td, 1H, H ), 7.11 (dd, 1H, H ), 7.15
7’ 7 6
13
m, 5H, H6’,8,8’), 7.58 (dd, 1H, H ), 7.62 (dd, 1H, H ).
C
4
2
General procedure for microwave-assisted Duff
formylation reaction of phenothiazine derivatives
NMR (75.4 MHz, CDCl ) d: 26.73 (CH ), 26.77 (CH ),
3
2
2
2
1
1
1
6.99 (CH ), 27.07 (CH ), 47.41 (CH ), 48.10 (CH ),
2 2 2 2
The reaction mixture (5 mmol phenothiazine derivative
and 7.5 mmol urotropine) dissolved in 20 mL acetic acid
was introduced into the quartz reaction vessel, which was
then sealed and subjected to microwave irradiation in the
resonance cavity of the microwave power system. Prescribed
sample temperatures were automatically monitored during
the irradiation (Table 1). TLC was used to monitor the reac-
tion progress. After irradiation, the reaction mixture was
poured into water and neutralized with Na CO . Organic
15.29 (CH, C ), 115.90 (2CH, C1’,9’), 116.44 (CH, C9),
1
22.83 (2Cquat, C ), 124.01 (C , C ), 124.38 (CH, C ),
4a’
quat
5a
7
25.60 (Cquat, C ), 127.60 (2CH, C2’,8’), 127.91 (2CH,
4a
C4’,6’), 127.98 (CH, C ), 128.00 (CH, C ), 128.82 (CH, C ),
6
4
8
1
1
30.0 (CH, C ), 131.50 (CH, C ), 143.84 (2C , C ),
2 3 quat 9a’
45.70 (Cquat, C ), 151.14 (Cquat, C10a), 190.40 (CH, CHO).
9a
Anal. calcd. for C H N OS (508.6) C 73.20, H 5.55, N
31
28
2
2
5
.51, found: C 73.18, H 5.55, N 5.61.
2
3
products were extracted in dichloromethane (3 ꢀ 20 mL).
8-Chloro-10H-phenothiazine-3-carbaldehyde (5a)
The combined organic layers were dried on anhydrous
Yellow precipitate recrystallized from toluene, mp
Na SO and concentrated to dryness. The product was puri-
1
2
4
195 8C. H NMR (300 MHz, CDCl , ppm) d: 9.65 (s, 1H,
3
fied by column chromatography (silica gel, toluene).
3
4
CHO), 7.51 (dd, J = 8.4 Hz , J = 1.6 Hz, 1H, H ), 7.37 (d,
J = 1.6 Hz, 1H, H ), 6.92 (d, J = 8.4 Hz, 1H, H ),
.84 (dd, J = 8.4 Hz , J =2 Hz, 1H, H ), 6.73 (d, J =
8.4 Hz, 1H, H ), 6.71 (d, J = 2 Hz, 1H, H ). C NMR
2
4
3
4
6
10H-Phenothiazine-3-carbaldehyde (1)
3
4
3
6
7
4
13
Yellow precipitate recrystallized from toluene, mp
1
9
1,26
1
1
1
7
8
92 8C.1
H NMR (300 MHz, CDCl , ppm) d: 9.24 (s,
(75.4 MHz, CDCl , ppm) d: 114.59 (CH, C ), 114.49 (CH,
3 1
3
4
3
H, NH), 9.64 (s, 1H, CHO), 7.50 (dd, J = 1.2 Hz, J =
.6 Hz, 1H, H ), 7.35 (s, 1H, H ), 7.00 (t, J = 7.6 Hz, J =
Hz, 1H, H ), d7.90 (d, J = 8 Hz, 1H, H ), 6.80(t, J =
C ), 122.76 (CH, C ), 127.63 (CH, C ), 124.74 (CH, C ),
9 7 6 2
3
3
2
4
130.78 (CH, C ), 190.39 (CH, CHO), 115.19 (C , C ),
4 quat 5a
3
3
116.82 (Cquat, C ), 132.28 (C , C ), 131.15 (Cquat, C3),
8
6
5a 8
quat
Published by NRC Research Press

4
8
Can. J. Chem. Vol. 88, 2010
4
3
1
41.24 (Cquat, C ), 146.35 (Cquat, C10a). Anal. calcd. for
CH ), 7.47 (d, 1H, H , J = 1.6 Hz), 7.36 (t, 1H, H , J =
9a
3
1
8
3
C H ClNOS (261.7): C 59.66, H 3.08, N 5.35; found: C
7.6 Hz), 7.35 (dd, 1H, H , J = 7.6 Hz), 7.26 (m, 2H, H ),
1
3
8
4 3,6
4
3
5
2
1
9.59, H 3.08, N 5.38.
7.17 (td, 1H, H , J = 1.6 Hz, J = 7.6 Hz), 7.13 (dd, 1H,
7
H , J = 2 Hz, J = 8.4 Hz). C NMR (CDCl , ppm) d:
4
3
13
9
3
-Chloro-10H-phenothiazine-3-carbaldehyde (5b)
2
2.98 (CH ), 169.07 (C=O), 132.57 (CH,C ), 139.87 (Cquat,
3
2
Brown precipitate recrystallized from toluene, mp 224 8C.
C10a), 138.60 (Cquat, C ), 127.54 (Cquat), 127.09 (2CH),
9a
H NMR (300 MHz, CDCl , ppm) d: 9.42 (s, 1H, NH), 9.96
3
128.45 (CH), 128.06 (CH), 127.27 (CH, C), 127.96 (CH,
C). Anal. calcd. for C H ClNOS (275.7): C 69.98, H 3.66,
N 5.08; found: C 69.89, H 3.66, N 5.19.
3
3
(s, 1H, CHO), 7.27 (s, 1H, H ), 7.01 (t, J = 7.2 Hz, J =
4
14
10
3
3
8
7
Hz, 1H, H ), 6.91 (d, J = 7.6 Hz, 1H, H ), 6.83 (t, J =
8 6
3
13
.6 Hz, J = 7.2 Hz, 1H, H ), 6.66 (m, 2H, H ). C NMR
7
1,9
(
75.4 MHz, CDCl , ppm) d: 113.64 (CH, C ), 115.09 (Cquat,
1-(2-(Trifluoromethyl)-10H-phenothiazine-10-yl)ethanone
(9)
3
9
C ), 115.93 (CH, C ), 115.26 (C , C ), 123.29 (CH, C ),
5
a
1
quat
4a
7
1
25.18 (CH, C ), 126.03 (CH, C ), 126.28 (CH, C ), 127.69
1
6
8
4
H NMR (300 MHz, CDCl , ppm) d: 2.21 (s, 3H, CH ),
3 3
(Cquat, C ), 136.35 (C , C ), 138.01 (C , C ), 147.16
3
3
3
quat
2
quat
9a
7.81 (s, 1H, H ), 7,25 (td, 1H, H , J = 7.6 Hz, J = 7.7 Hz,
J = 1.6 Hz), 7.34 (td, 1H, H , J = 8 Hz, J = 7.7 Hz, J =
1.6 Hz), 7.51 (d, 1H, H , J = 8.4 Hz), 7.46 (m, 2H, H ).
C NMR (CDCl , ppm) d: 22.88 (CH ), 169.13 (C=O),
1 7
(
Cquat
,
C10a), 186.27 (CH, CHO). Anal. calcd. for
4
3
3
4
8
C H ClNOS (261.7): C 59.66, H 3.08, N 5.35; found: C
3
1
3
8
4 4,9
5
9.59, H 3.08, N 5.38.
13
3
3
1
29.49 (CH, C ), 123.45 (C , CF ), 124.46 (Cquat), 125.10
2 quat 3
2
-(Trifluoromethyl)-10H-phenothiazine-3,7-dicarbaldehyde
(
1
Cquat), 139.05 (Cquat, C10a), 138.42 (Cquat, C ), 127.09 (CH),
27.31 (2 CH), 127.57 (2 CH), 128.12 (CH), 128.17 (CH).
9a
(6)
1
H NMR (300MHz, CDCl , ppm) d: 9.42 (s, 1H, NH),
3
Anal. calcd. for C H F NOS (309.3): C 58.25, H 3.26, N
4
15
10 3
9
7
1
.96 (s, 1H, CHO), 10.35 (s, 1H, CHO), 7.39 (s, 1H, H ),
4
.53, found: C 58.14, H 3.26, N 4.61.
3
4
2
.54 (dd, J = 7.2 Hz, J = 1.2 Hz 1H, H ), 7.46 (d, J =
.2 Hz, 1H, H ), 7.06 (s, 1H, H ), 7,39 (d, J = 7.2 Hz, 1H,
8
3
6
1
1-(10-Methyl-10H-phenothiazine-3yl)ethanone (10)
13
H9). C NMR (75.4 MHz, CDCl , ppm) d: 115.95 (CH, C ),
21
1H NMR
3
1
Recrystallized from toluene, mp 101 8C.
1
1
1
1
1
20.64 (CH, C ), 118.09 (C , C ), 122.26 (Cquat, C4a),
9 quat 5a
31.29 (Cquat, C ), 130.18 (CH, C ), 129.03 (CH, C ),
31.28 (CH, C ), 121.69 (C , C ), 128.35 (Cquat, C2),
48.01 (Cquat, C ), 148.16 (Cquat, C10a), 190.27 (CH, CHO),
(
300 MHz, CDCl , ppm) d: 2.51 (s, 3H, CH ), 3.39 (s, 3H,
3
3
7
6
8
3
H C), 6.7 (d, 1H, H ), 7.76 (d, J = 8.4 Hz, 1H, H ), 7.69
3
1
2
4
quat
3
3
3
(
s, 1H, H ), 7.12 (d, J = 6.7 Hz, 1H, H ), 6.97 (t, J =
.2 Hz, J = 7.6, 1H, H ), 7.17 (t, J = 7.6 Hz, 1H, H ),
4
6
9a
3
3
7
6
3
7
8
91.34 (CH, CHO). Anal. calcd. for C H F NO S (323.2):
3
13
1
5
8
3
2
.82 (d, J = 7.6 Hz, 1H, H ). C NMR (CDCl , ppm) d:
9
3
C 55.73, H 2.49, N 4.33; found: C 55.69, H 2.49, N 4.42.
5.62 (CH ), 26.22 (CH ), 113.31 (CH, C ), 128.77 (CH,
3
3
1
C ), 131.58 (CH, C ), 123.19 (C , C ), 122.63 (Cquat,
2
3
quat
4a
General procedure for microwave-assisted acetylation
reaction of phenothiazine derivatives
C ), 127.23 (CH, C ), 123.33 (CH, C ), 127.30 (CH, C ),
5a
6
7
8
1
1
7
14.53 (CH, C ), 127.66 (CH, C ), 144.46(Cquat, C9a),
9 4
The reaction mixture (phenothiazine derivative – acetic
anhydride ratio 1:10 and phosphoric acid in catalytic
amounts) was introduced into the quartz reaction vessel,
which was then sealed and subjected to microwave irradia-
tion in the resonance cavity of the microwave power system.
Prescribed sample temperatures were automatically moni-
tored during the irradiation (Table 2). TLC was used to
monitor the reaction progress. After irradiation, the reaction
mixture was poured on ice and neutralized. The precipitate
formed was filtered and thoroughly washed with water. The
product was purified by recrystallization in toluene.
49.85 (Cquat, C ) Anal. calcd. for C H NOS (255.3): C
10a .
15 13
0.56, H 5.13, N 5.49; found: C 70.46, H 5.13, N 5.55.
1
,1’-(10-Methyl-10H-phenothiazine-3,7-diyl)diethanone
(
11)
Yellow-green precipitate recrystallized from toluene
31
1
(
64 % yield), mp 202 8C.
H NMR (300 MHz, CDCl ,
3
2
ppm) d: 2.54 (s, 6H, CH ), 3.46 (s, 3H, CH ), 6.84 (d, J =
3
3
2
1
0 Hz, 2H, H ), 7.70 (s, 2H, H ), 7.79 (d, J = 10 Hz, 2H,
1,9 4,6
13
H ). C NMR (CDCl , ppm) d: 26.7 (CH ), 36.4 (CH ),
2,8
3
3
3
1
14.4 (CH, C ), 123.3 (C , C ), 127.8 (CH, C ), 129.1
1,9 quat 4a 4,6
(
(
CH, C ), 132.9 (C , C ), 148.9 (C , C ), 196.4
2,8 quat 3,7 quat 9a
1
1
-(10H-Phenothiazine-10-yl)ethanone (10-acetyl-
0Hphenothiazine) (7)
Cquat, CO). Anal. calcd. for C H NO S (297.3): C 68.66,
17
15
2
H 5.08, N 4.71; found: C 68.59, H 5.08, N 4.78.
White crystals recrystallized from toluene, mp 199 8C.29
1
H NMR (300 MHz, CDCl , ppm) d: 2.13 (s, 3H, CH ),
3
3
Acknowledgments
3
3
7
7
7
.62 (d, J = 8 Hz, 2H, H ), 7.40 (t, J = 8 Hz, 2H, H ),
.31 (t, J = 7.2 Hz, J = 7.6 Hz, 2H, H ), 7.56 (d, J =
1,9 2,8
3
3
3
The authors thank the Romanian Government for finan-
cial support (grant ID_564).
3
,7
13
.6 Hz, 2H, H ). C NMR (CDCl , ppm) d: 127.93 (CH,
4,6
3
C ), 126.95 (CH, C ), 126.67 (CH, C ), 127.17 (Cquat, C5a),
1
2
3
References
22.39 (CH ), 169.27 (Cquat, CO), 138.94 (Cquat, C10a). Anal.
3
calcd. for C H NOS (241.3): C 69.68, H 4.59, N 5.80;
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14
11
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(
(
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White precipitate recrystallized from toluene, mp
04 8C.3 H NMR (300 MHz, CDCl , ppm) d: 2.13 (s, 3H,
0 1
1
3
Published by NRC Research Press

Gaina et al.
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Published by NRC Research Press