Heterocyclization of N-propenyl-substituted phenothiazines and phenoxazines using electrophiles in an anhydrous medium

Article abstract of DOI:10.1007/s10593-009-0219-5

10-Propenylphenothiazine reacts with a catalytic amount of BF ₃·Et₂O in dry ethyl acetate via intramolecular heterocyclization of an intermediate dimeric cation to give mainly 1-ethyl-2-methyl-3-(phenothiazin-10-yl)-2,3-dihydro-1H-pyrido[3,2,1-k,l] phenothiazine and a minor product through fission of phenothiazine which is 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenothiazine. Under similar conditions 10-propenylphenoxazine gave an oligomer (degree of polymerization 4.4) and the minor product 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenoxazine likely formed similarly to the phenothiazine analog from the corresponding product of intramolecular heterocyclization (the latter not being observed in the reaction mixture).

Full text of DOI:10.1007/s10593-009-0219-5

Chemistry of Heterocyclic Compounds, Vol. 44, No. 12, 2008
HETEROCYCLIZATION OF N-PROPENYL-
SUBSTITUTED PHENOTHIAZINES AND
PHENOXAZINES USING ELECTROPHILES
IN AN ANHYDROUS MEDIUM
E. E. Sirotkina1, A. I. Khlebnikov2, and O. A. Napilkova2
10-Propenylphenothiazine reacts with a catalytic amount of BF3·Et2O in dry ethyl acetate via
intramolecular heterocyclization of an intermediate dimeric cation to give mainly 1-ethyl-2-methyl-
3-(phenothiazin-10-yl)-2,3-dihydro-1H-pyrido[3,2,1-k,l]phenothiazine and a minor product through
fission of phenothiazine which is 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenothiazine. Under similar
conditions 10-propenylphenoxazine gave an oligomer (degree of polymerization 4.4) and the minor
product 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenoxazine likely formed similarly to the phenothiazine
analog from the corresponding product of intramolecular heterocyclization (the latter not being
observed in the reaction mixture).
Keywords: 1H-pyrido[3,2,1-k,l]phenoxazines, 1H-pyrido[3,2,1-k,l]phenothiazines, propenyl-substi-
tuted, phenoxazine, phenothiazine, heterocyclization, electrophilic catalysts.
The high interest in the chemistry of phenothiazine and phenoxazine is due in many ways to the
biological activity of their derivatives [1-5]. We have previously reported the prototropic isomerization of
N-allyl derivatives of phenothiazine and phenoxazine to give cis-10-propenylphenothiazine (1) [6] and
cis-10-propenylphenoxazine (2) [7]. In the case of the acid hydrolysis of these compounds it has been shown [8]
that they demonstrate an increased activity with relation to electrophilic reagents while the initial position of
attack of a proton to form the carbenium-immonium intermediate of type A is the α-carbon atom of the
substituent (Scheme 1).
Scheme 1
X
N
X
N
BF3·Et2O
+
1, 2
A1, A2
1, A1 X = S, 2, A2 X = O
_______
* Dedicated to Academician of the Russian Academy of Sciences B. A. Trofimov on his jubilee.
__________________________________________________________________________________________
1Institute of Petroleum Chemistry, Siberian Branch of the Russian Academy of Sciences, Tomsk
2
634021, Russia; e-mail: see@ipc.tsc.ru. I. I. Polzunov Altai State Technical University, Barnaul 656038,
Russia; e-mail: aikhl@chem.org.ru. Translated from Khimiya Geterotsiklicheskikh Soedinenii, No. 12, pp.
1855-1860, December, 2008. Original article submitted May 23, 2008.
0009-3122/08/4412-1505©2008 Springer Science+Business Media, Inc.
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Stabilization of ion A is achieved by conjugation of the vacant p-orbital with the unshared electron pair
of the nitrogen atom, the stabilization being more efficient for ion A1 than for ion A2 [9]. The intermediates A
are readily hydrolyzed in aqueous media to the corresponding heterocycle and propionaldehyde [8]. In this work
we have studied the conversion of compounds 1, 2 with the electrophilic catalyst BF3·Et2O in anhydrous ethyl
acetate.
Through an initial TLC investigation of the action of an electrophilic catalyst (H2SO4, P2O5, BF3·Et2O)
on compound 1 in various solvents (toluene, ethyl acetate, DMF, methylene chloride) it was found that the
process route depended markedly on the amount of the catalyst. High concentrations of catalyst (2×10-2 to
0.1 molar) basically gives phenothiazine and tarry products. Direction of the course of the process proved
possible by the use of BF3·Et2O in concentrations around 10-3 molar in an anhydrous solvent. The main reaction
product of propenylphenothiazine
1 is 1-ethyl-2-methyl-3-(phenothiazin-10-yl)-2,3-dihydro-1H-pyrido-
[3,2,1-k,l]phenothiazine (3), evidently formed through an intramolecular alkylation in the intermediate dimer
cation B1 according to Scheme 2. A similar reaction has been reported before for cis-9-propenylcarbazole [1].
Scheme 2
S
N
+
1
A1
+
+
N
–H
S
7
8
6
B1
S
S
S
4
N
11
1"
+
+
1
2
N
N
N
3
11
1"
H
1'
1
3
2'
S
2
1'
2'
3
4
For a targeted synthesis of compound 3 the most convenient solvent is ethyl acetate freshly distilled
from P2O5. This simplifies the separation of product 3 which is virtually insoluble in ethyl acetate and can be
filtered from the reaction mass.
The reaction occurs readily at room temperature leading to a 66-75% yield of product 3 after 2-3 h.
According to TLC data the reaction mixture shows compound 3, phenothiazine, and tarry products, and
also the previously unknown 1-ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenothiazine (4) having an Rf close to that
of the starting propenylphenothiazine. The oily product 4 was separated by a column chromatographic method.
The tetracyclic derivative 4 is evidently formed from 3 via fission of phenothiazine. The presence of the latter in
the reaction mixture agrees with this proposal.
The formation of product 4 was confirmed by us by independent experiments studying the thermal and
catalytic (BF3·Et2O) decomposition of compound 3. According to TLC data the reaction mixtures have the same
composition as in the condensation of the propenylphenothiazine 1. The composition and structure of
compounds 3 and 4 are confirmed by the results of elemental analysis, IR spectroscopic data (for compound 3),
and also from their 1H and 13C NMR spectra (see Experimental section).
1506

It is obviously that compounds 3 and 4 are convenient intermediate products for the preparation of
various pyridophenothiazines. Promising use has been shown for the pyridophenothiazines 3, 4 in increasing the
thermooxidative stability of lubricating oils and as polyolefine stabilizers [11].
By contrast with compound 1 the product 5 (analog of compound 3) is not found in the action of
BF3·Et2O in dry ethyl acetate on the propenylphenoxazine 2 but there occurs a rather ready oligomerization of
monomer 2 at the double bond. A thermostable oligomer with a softening temperature of 180-200ºC was
obtained in 23% yield at 0ºC after 18 min. Increasing the temperature up to 60ºC and continuing the process for
80 h did not significantly affect the yield of the oligomer product. The molecular weight of the oligomer was
determined by the Rast method (in camphor) as 980 g/mol which corresponds to a mean degree of polymerisation
of 4.4. The IR spectrum of the oligomer shows the absence of absorption bands for C=C and N–H bonds and the
presence of bands at 1610 and 740 cm-1 assigned respectively to stretching vibrations of the aromatic rings and to
deformation of the 1,2-disubstituted benzene ring. On this basis it can be confirmed that oligomerization of the
10-propenylphenoxazine 2 is not complicated by rearrangement of the cation arising as happens in the case of
9-isobutenylcarbazole or 9-styrylcarbazole [12]. The oligomer obtained forms films which have good adhesion
to glass and metals and can be used in electrophotography since it is known that polyalkenyl-phenoxazines are
organic photosemiconductors [13, 14].
Scheme 3
O
N
O
N
+
2
A2
+
N
N
–H+
O
O
B2
5
O
O
+
N
N
11
H
1
1"
3
1'
2
2'
6
The oligomer was separated via precipitation from the reaction mixture with ethyl alcohol and subsequent
filtration. Column chromatography of the filtrate on silica gel also gave a 13.5% yield of the 1-ethyl-2-methyl-
1H-pyrido[3,2,1-k,l]phenoxazine (6). It is likely that, along with the oligomerization of monomer 2 similarly to
compound 1, there occurs an intramolecular alkylation of the dimer cation B2 arising to give the intermediate
1-ethyl-2-methyl-3-(phenoxazin-10-yl)-2,3-dihydro-1H-pyrido[3,2,1-k,l]phenoxazine (5). Separation of phenoxazine
under the reaction conditions gives compound 6 (Scheme 3). The presence of unsubstituted phenoxazine in the
reaction mixture is shown by TLC. The relative ease of formation of product 6 is a feature of the oligomerization of
the alkenylphenoxazine 2 since, in the series of carbazole [10] and phenothiazine dimers, similar to compound 5, are
stable, high-melting materials.
The composition and structure of compound 6 are confirmed by the results of elemental analysis and
also by their IR, 1H and 13C NMR spectra, similarly to that of compound 4.
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EXPERIMENTAL
1
IR spectra were recorded on an IRS-29 spectrophotometer. H NMR spectra were taken on a Bruker
AV300 (300 MHz) instrument and 13C NMR spectra on a WP-200 (50 MHz) under conditions of complete
suppression of 1H–13C spin-spin interactions with HMDS (δ 0.05 ppm) as internal standard. TLC was carried out
using Silufol UV-254 plates with eluent hexane-ether (12:1) for the phenothiazine compounds or hexane–
benzene (5:3) for the phenoxazine compounds.
1-Ethyl-2-methyl-3-(phenothiazin-10-yl)-2,3-dihydro-1H-pyrido[3,2,1-k,l]phenothiazine (3).
A
solution (0.5 ml) of BF3·Et2O (0.15 mmol in ethyl acetate) was added to a solution of compound 1 (12 g,
30 mmol) in anhydrous ethyl acetate (50 ml). The reaction mixture was held for 2 h 18 min at room temperature.
The precipitate formed was filtered off and washed successively with ethyl acetate (10 ml) and ethanol (50 ml)
to give compound 3 (8.4 g, 70%) as white crystals with mp 210-212ºC. Compound 3 is readily soluble in
chloroform and benzene and poorly in ethyl acetate, acetone, and hexane. IR spectrum (KBr), ν, cm-1: 760
(1,2-disubstituted benzene ring), and 790 and 740 (1,2,3-trisubstituted benzene ring). NH group absorption
bands were absent. 1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 1.08 (3H, t, J = 8, CH3CH2); 1.28 (3H, d, J = 7,
CH3); 1.60 (2H, m, CH3CH2); 2.70 (1H, m, H-2); 4.10 (1H, m, H-1); 4.96 (1H, d, J = 5, H-3); 6.60-6.70 (15H,
m, Harom). 13C NMR spectrum (CDCl3), δ, ppm: 11.53 (C-1"); 15.95 (C-2'); 20.80 (C-1'); 29.77 (C-2); 61.33
(C-1); 63.64 (C-3); 114.19 (C-11); 126.29 (C-3'). The signals for the remaining C atoms of the phenothiazine
fragments occurred in the region 122-147 ppm. Found, %: C 75.65; H 5.69; N 5.51; S 13.01. C30H26N2S2.
Calculated, %: C 75.28; H 5.47; N 5.85; S 13.40.
1-Ethyl-2-methyl-1H-pyrido[3,2,1-k,l]phenothiazine (4). After distillation of the solvent from the filtrate
from the synthesis of compound 3 the residue was loaded onto an L 100/160 silica gel column (70×2 cm) and
1
eluted with a mixture of hexane and ether (2:1) to give compound 4 (0.63 g, 9%) with mp 69-70ºC (hexane). H
NMR spectrum (acetone-d6), δ, ppm (J, Hz): 0.96 (3H, t, J = 8, CH3CH2); 1.60 (2H, m, CH3CH2); 2.04 (3H, s,
CH3); 4.54 (1H, dd, J = 5, J = 3, H-1); 6.20 (1H, s, H-3); 6.60-6.70 (7H, m, Harom). 13C NMR spectrum (acetone-d6),
δ, ppm: 10.06 (C-1"); 21.12 (C-1'); 26.76 (C-2'); 60.39 (C-1); 114.33 (C-11); 120.25 (C-3); 125.25 (C-3'); 136.17
(C-2). The signals for the remaining carbon atoms of the phenothiazine fragments were found in the range 122-147
ppm. Found, %: C 77.54; H 6.29; N 5.22. C18H17NS. Calculated, %: C 77.38; H 6.13; N 5.01.
Dimerization and Oligomerization of cis-10-Propenylphenoxazine (2). A mixture of compound 2
(3 g, 13.5 mmol) and anhydrous ethyl acetate (23 ml) was heated to 60ºC after which 4 ml of a 0.0894 M
solution of BF3.Et2O in ethyl acetate was added to it. After 1 h 40 min the initiator was neutralized with a
solution of sodium propionate in propyl alcohol. The reaction mixture was poured into ethanol (120 ml), held
for 24 h, and filtered. The precipitate was washed with cold ethanol and dried at 50ºC at a pressure of 25-40 hPa
to give an oligomer (0.64 g, 21%) as a light-brown, amorphous powder with a softening temperature of
180-200ºC. The filtrate was evaporated to dryness and the residue was transferred to an L 100/160 silica gel
column (70×2 cm). It was eluted with a mixture of hexane and benzene (5:3) to give compound 6 (0.29 g,
13.5%) with mp 121-122ºC (hexane). IR spectrum (KBr), ν, cm-1: 1660 (C=C), 750 (1,2-disubstituted benzene
ring), and 730 and 780 cm-1 (1,2,3-trisubstituted benzene ring). Absorption bands for NH groups were absent.
1H NMR spectrum (CDCl3), δ, ppm (J, Hz): 0.92 (3H, t, J = 7.5, CH3CH2); 1.68 (2H, m, CH3CH2); 1.75 (3H, s,
CH3); 4.45 (1H, t, J = 4, H-1); 6.01 (1H, s, H-3); 6.20-6.80 (7H, m, Harom.). Found, %: C 81.92; H 6.38; N 5.14.
C18H17NO. Calculated, %: C 82.10; H 6.51; N 5.32.
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