Synthesis of new n-alkyl- and n-acyldioxinophenothiazine and acridinone derivatives

Article abstract of DOI:10.3987/com-00-9013

The synthesis of new substituted dioxino[b]- and [c]phenothiazines or acridinones is reported. N-Arylation of [1,4]benzodioxin-6-amine with organolead or organobismuth reagents gave N-aryl-2,3-dihydro-1,4-benzodioxin-6-amine; subsequent Bernthsen thionati

Full text of DOI:10.3987/com-00-9013

HETEROCYCLES, Vol. 53, No11, 2000, pp. 2535 - 2552, Received, 19th July, 2000
SYNTHESIS
OF
NEW
N-ALKYL-
AND
N-ACYLDIOXINO-
PHENOTHIAZINE AND ACRIDINONE DERIVATIVES
*
Florence Chatel, Sandrine Morel, Gérard Boyer, and Jean Pierre Galy
UMR 6009, Laboratoire de Valorisation de la Chimie Fine, case 552, Université
Aix-Marseille III, avenue Escadrille Normandie-Niemen, 13397 Marseille Cedex
20, France
Abstract - The synthesis of new substituted dioxino[b]- and [c]phenothiazines or
acridinones is reported. N-Arylation of [1,4]benzodioxin-6-amine with organolead
or organobismuth reagents gave N-aryl-2,3-dihydro-1,4-benzodioxin-6-amine;
subsequent Bernthsen thionation led to phenothiazine ring formation, followed by
N-acylation. On the other hand [1,4]benzodioxin-6-amine was first N-alkylated
and the resulting alkylamines were N-phenylated before Bernthsen thionation to
provide the tetracyclic phenothiazines. Alternative arylation with chlorobenzoic
acid followed by cyclization under acidic conditions afforded the
dioxinoacridinones, which were successfully alkylated.
INTRODUCTION
Acridine derivatives are well known therapeutic agents because of their wide range of pharmacological
and biological activities, and many derivatives have been reported as being neuroleptics1 or anticancer
agents.2 The interest in tetracyclic derivatives has increased in the last few years;3 we previously reported
the preparation of new compounds bearing a pyrazole,4 a cyclopentane,5 or a dioxole fourth ring fused to
a phenothiazine or acridine moiety. Herein we report the preparation of N-substituted tetracycles bearing
a dioxane ring.
RESULTS AND DISCUSSION
To our knowledge there have been few syntheses of linear dioxino[2,3-b]acridines, but without N-
substitution.6 Our approach is based on the N-arylation of commercial [1,4]benzodioxin-6-amine (1) with
organolead and organobismuth reagents,7 in the presence of copper catalyst, followed by cyclization by
Bernthsen thionation of the corresponding N-aryl[1,4]benzodioxin-6-amines (3). In the same way,
coupling of benzoic acid with 1, followed by cyclization in acidic media led to the dioxinoacridinones

(4-5).
The first key step is the synthesis of diarylamines (3a-e) by copper catalysis. For this purpose we used the
Ullmann conditions but yields of desired products were low;8 on the other hand, a modified procedure
using organolead or organobismuth derivatives led us to significantly improve the yield of this N-
arylation step.9 With p-tolyllead triacetate (2a) and 4-methoxyphenyllead triacetate (2b), we obtained the
corresponding coupling products N-4-methylphenyl-[1,4]benzodioxin-6-amine (3a) and N-4-
methoxyphenyl-[1,4]benzodioxin-6-amine (3b) (43-51 % yield) (Scheme 1). The Naryl[1,4]benzodioxin-
6-amine (3c-d) were prepared in the same manner using the arylbismuth reagents (2c-d) (62 and 32 %
yields respectively).
O
R1
R2
O
R2
R1
Cu(OAc)2
CH2Cl2, rt
+
H2N
O
N
H
O
R3
n
1
3a-e
2a-e
Scheme 1
Table 1: Synthesis of N-arylamine derivatives (3a-e)
Compound No
R
R
R
3
n
Products
obtained
3a
1
2
CH3
OCH3
H
Cl
H
H
H
H
Pb(OAc)
Pb(OAc)
Bi(OAc)
Bi(OAc)
Cl
1
1
3
3
1
2a
2b
2c
2d
2e
3
3
3b
3c
3d
3e*
2
2
H
COOH
* Cu, 1-pentanol, 110°C
The cyclization of 3a-d was performed by Bernthsen thionation in refluxing o-dichlorobenzene with
sulfur and iodine. Usually a mixture of two isomers can be obtained owing to two possible cyclization
sites in the [1,4]benzodioxol moiety; thus, cyclization of derivatives (3) would lead to a linear [b]fused
phenothiazine isomer (cyclization at position 7) and to an angular [a]fused isomer (cyclization at position
5) (Scheme 2). Indeed, cyclization of 3a and 3b turned out to be regioselective and led to a single isomer,
the linear 8-methyl-11H-[1,4]dioxino[2,3-b]phenothiazine (4a) and 8-methoxy-11H-[1,4]dioxino[2,3-
b]phenothiazine (4b) (47 and 29 % respectively); in contrast, with 2c, a mixture of both angular and
linear isomers (4c) and (5c), which could not be separated, was obtained (43 % crude yield, isomeric
ratio 60/40). Cyclization of the chloroaryl amine (3d) was unsuccessful, leading to many side products of
2
degradation.
1O
12a
3
4
O
6
S
7
13
5
12
S
8
11
8
12b
5a
4a
6a
R1
8
10
R1
R2
O
O
11a
7a
R1
O
4
S8, I2
2
3
3
2
12
7
+
11
7
9
9
5
11
1,2-Cl2C6H4,
reflux
10a
11a
12a
6a
N
H
O
1
6
N
H
N
10
12
10
5
6
9H
Scheme 2
3a-d
4a-c
5c

Table 2: Synthesis of phenothiazine derivatives (4a-c, 5c).
Compound No
R
R
Products
obtained
4a
4b
4c/5c
-
1
2
CH
OCH
H
Cl
H
3a
3b
3c
3d
3
H
H
H
3
The assignment of the linear and angular structures of the fused tetracycles was determined
unambiguously by the 1H-NMR spectra, in particular by the evaluation of the multiplet pattern of the C-
ring proton signals: In the case of [b] fusion, 5-H and 12-H are expected to resonate as singlets, whereas
two doublets (AB quartet, J = 8 Hz) would be expected in the case of [a] fusion (5-H and 6-H) (Scheme
2). In fact, this former pattern was observed, for example with two singlets at δ 6.25 and 6.47 ppm (12-H
and 5-H) for 8-methyl-11H-[1,4]dioxino[2,3-b]phenothiazine (4a); in contrast two doublets at δ 6.16 and
6.48 ppm prove the angular fused structure of 7H-[1,4]dioxino[2,3-c]phenothiazine (5c).
The tetracyclic acridinones (4-7) were also obtained by cyclization but with Friedel-Crafts acylation of
the anthranilic acid (3e) under acidic conditions (Scheme 3). A mixture of both isomers was obtained
with a reversed isomeric ratio depending on the solvent. Effectively, performing the reaction in
polyphosphoric acid (PPA) or sulfuric acid led, after chromatography separation, to the angular 7H-
[1,4]dioxino[2,3-a]acridin-12-one (5e) (43 % yield), and the linear 6H-[1,4]dioxino[2,3-b]acridin-11-one
(4e) (28 % yield). On the other hand, cyclization with phosphorous oxychloride led to the chloro
derivatives (6a) and (7a) with 32 and 20 % yields respectively after purification.
2
1O
3
O
O
1
O
10
12
5
O 4
H2SO4/PPA
80-110°, 2 h
9
8
2
3
11
+
6
N
5
O
4
N
H
7
6
H
COOH
O
O
4e
5e
7
2
N
H
1O
5
3
Cl
Cl
1
O
12
5
O 4
2
3
3e
POCl3
+
120°, 0.5 h
N
N
O
4
6a
7a
Scheme 3
The next step involved the conversion of the phenothiazines (4) and (5) into N-alkylaminoalkyl and N-
acyl derivatives. Previously described preparative procedures for direct N-aminoalkylation of similar
dioxolophenothiazines10 with sodium amide in xylene or sodium hydride and N,N-dimethylaminoalkyl

halides in DMSO, or phase transfer catalysis11 were unsuccessful. Direct N-alkylation of the N-
aryl[1,4]benzodioxin-6-amines (3a-d) before cyclization was also attempted but the desired products
were not obtained. We therefore decided to monoalkylate the aromatic amine (1) with different alkyl
halides in the presence of sodium hydrogen carbonate in acetonitrile.12 1-Bromobutane and 1-bromo-3-
methylbutane gave N-butyl- and N-isopentyl[1,4]benzodioxin-6-amines (8a and 8b) (48-50 %).
Compounds (8c) and (8d) were prepared in the same way (15-38 %). Next, the reaction of 8a-d with
triacetates (2a-b) or
triphenylbismuth diacetate (2c) led to the corresponding N-alkyl-N-
aryl[1,4]benzodioxin-6-amines (9a-g) (Scheme 4).
R1-Br,
R2
O
O
O
O
O
2a-c
NaHCO3
HN
R1
Cu(OAc)2,
CH2Cl2, rt
CH3CN,
reflux
N
R1
H2N
O
9a-g
1
8a-d
S8, I2
R2
S
O
9a-g
1,2-Cl2C6H4,
reflux
N
R1
O
10a-b, 10d
Scheme 4
Table 3: Synthesis of N-alkyl phenothiazine derivatives (10a-b, 10d)
R
1
R
2
8
9
10
(CH2)3CH3
(CH2)3CH3
(CH2)3CH3
H
OCH
CH
H
H
1
8a
8a
8a
8b
8c
8d
8d
9a
9b
9c
9d
9e
9f
10a
10b
-
3
3
(CH2)2CH(CH3)2
CH(CH3)2
CH(CH3)(CH2)2CH3 CH
10d
-
-
-
3
CH(CH3)(CH2)2CH3
H
9g
Under Bernthsen's condition, only three arylamines (9a, 9b and 9d) were cyclized to regioselective linear
fused phenothiazine products (10a, 10b and 10d) (11-17 %). By contrast 9c, 9e, 9f and 9g led to
degradation products only.
Acylation of 4a-c performed with chloroacetyl chloride in toluene, followed by condensation with N,N-
diethylamine provided the corresponding N-(2-diethylaminoacetyl) derivatives (11a-c) (52-69 %)
R
S
O
(Scheme 5).
1) ClCH2COCl,
CH3Ph, reflux
R
S
O
O
N
O
2) C2H5NH,
N
H
a: R = CH3
b: R = OCH3
c: R = H
O
CH3Ph, reflux
4a-c
11a-c
N
C2H5
C2H5
Scheme 5

N-Alkylacridinones (12-15) were obtained by direct alkylation of a mixture of both linear and angular
dioxinoacridinones (4e) and (5e), followed by chromatographic separation. With dimethyl sulfate in
acetone,13 the tetracycles (12a) and (13a) were obtained (28 and 43 % yields after separation); in
contrast, phase transfer catalysis in toluene with 2-dimethylaminoethyl chloride hydrochloride yielded
the
6-[2-dimethylaminoethyl]-6H-[1,4]dioxino[2,3-b]acridin-11-one
(14a)
and
the
7-[2-
dimethylaminoethyl]-7H-[1,4]dioxino[2,3-a]acridin-12-one (15a) (8 % each one) (Scheme 6).
O
O
O
O
O
O
CH3I
+
N
N
CH3
CH3
12a
13a
4e + 5e
O
O
O
O
O
O
Cl(CH2)2N(CH3)2
+
N
N
14a
15a
H3C
N
N
H3C
CH3
CH3
Scheme 6
CONCLUSION
We report the preparation of a new class of tetracyclic heterocycles, N-alkyl- and N-acyl-
[1,4]dioxino[2,3-b]phenothiazines and acridinones, employing organometalic reagents and benzoic acid
for N-arylation, followed by Bernthsen thionation or acidic condition for ring closure.
EXPERIMENTAL
1
13
Melting points were measured on a Mettler FP 61 apparatus and are uncorrected. The H- and C-NMR
spectra were measured on a Bruker 200 spectrometer. Chemical shifts were recorded as units relative to
tetramethylsilane as the internal standard. Separations by chromatography were performed on silica gel
(Merck, 70-230 mesh). [1,4]Benzodioxin-6-amine (1) is commercially available and was used as
received; triacetates (2a) and (2b) and diacetates (2c) and (2d) were prepared according to the
literature.14
N-(4-Methylphenyl)[1,4]benzodioxin-6-amine (3a)
To a solution of [1,4]benzodioxin-6-amine (1) (1 g, 6.6 mmol) in dry dichloromethane (40 mL) at rt were
slowly added p-tolyllead triacetate (2a) (3.5 g, 7.3 mmol) and copper(II) acetate (0.12 g, 0.66 mmol). The
mixture was stirred during 3 h at rt. Next, dichloromethane was added to the solution (20 mL) and the

resulting mixture was filtered. The insoluble part was washed with dichloromethane (2 x 20 mL), and the
organic layers were dried over anhydrous sodium sulphate and evaporated to give a crude reaction
product which was purified by chromatography on silica gel with toluene as the eluent. A white powder
1
was obtained, yielding 0.8 g (51 %) of 3a; mp 54°C (from toluene). H-NMR (DMSO-d ) δ: 2.19 (3H, s,
6
CH ), 4.16 (2H, m, 2-H), 4.20 (2H, m, 3-H), 6.52 (1H, dd, J = 2.6, 8.3 Hz, 7-H), 6.54 (1H, d, J = 2.6 Hz,
3
5-H), 6.72 (1H, d, J = 8.3 Hz, 8-H), 6.87 (2H, d, J = 8.4 Hz, 10-H and 14-H), 6.99 (2H, d, J = 8.2 Hz, 11-
13
H and 13-H), 7.69 (1H, s, 9-H). C-NMR (DMSO-d ) δ: 20.29 (CH ), 63.90 (2-C), 64.35 (3-C), 106.06
6
3
(5-C), 110.92 (7-C), 116.23 (2C, 10-C and 14-C), 117.33 (8-C), 127.67 (12-C), 129.59 (2C, 11-C and 14-
C), 137.12 (8a-C), 137.85 (6-C), 141.93 (9a-C), 143.62 (4a-C). Anal. Calcd for C15H15NO2: C 74.67; H
6.27; N 5.81. Found: C, 74.82; H, 6.53; N, 6.13.
N-(4-Methoxyphenyl)[1,4]benzodioxin-6-amine (3b)
As described above for 3a but with 1 (1 g, 6.6 mmol) and 4-methoxyphenyllead triacetate (2b) (3.6 g, 7.3
mmol). After work up, chromatography on silica gel with dichloromethane yielded 0.7 g (43 %) of 3b as
1
yellow needles; mp 90°C (from dichloromethane). H-NMR (DMSO-d ) δ: 3.69 (3H, s, OCH ), 4.15
6
3
(2H, m, 2-H), 4.18 (2H, m, 3-H), 6.43 (1H, dd, J = 2.6, 8.3 Hz, 7-H), 6.44 (1H, d, J = 2.6 Hz, 5-H), 6.69
(1H, d, J = 8.4 Hz, 8-H), 6.85 (2H, d, J = 8.9 Hz, 11-H and 13H), 6.91 (2H, d, J = 8.9 Hz, 10-H and 14H),
13
7.51 (1H, s, 9-H). C-NMR (DMSO-d ) δ: 55.16 (OCH ), 63.79 (2-C), 64.24 (3-C), 104.65 (5-C),
6
3
109.60 (7-C), 114.50 (2C, 11-C and 13-C), 117.25 (8-C), 118.87 (2C, 10-C and 14-C), 136.68 (8a-C),
137.41 (9a-C), 139.00 (6-C), 143.58 (4a-C), 153.14 (12-C). Anal. Calcd for C15H15NO3: C, 70.02; H,
5.88; N, 5.44. Found: C, 70.39, H, 5.47; N, 5.81.
N-Phenyl[1,4]benzodioxin-6-amine (3c)
As described above for 3a but with 1 (1 g, 6.6 mmol) and triphenylbismuth diacetate (2c) (1.35 g, 2.4
mmol). Purification was performed by chromatography with hexane/ethanol (60/40) to yield 0.95 g (63 %)
1
of 3c as white needles; mp 91°C (from ethanol). H-NMR (DMSO-d ) δ: 4.18 (2H, m, 2-H), 4.21 (2H,
6
m, 3-H), 6.56 (1H, dd, J = 2.6, 8.2 Hz, 7-H), 6.58 (1H, d, J = 2.5 Hz, 5-H), 6.72 (1H, m, 12-H), 6.75 (1H,
13
d, J = 8.2 Hz, 8-H), 6.94 (2H, m, 10-H and 14-H), 7.16 (2H, m, 11-H and 13-H), 7.83 (1H, s, 9-H). C-
NMR (DMSO-d6) δ: 63.92 (2-C), 64.33 (3-C), 107.03 (5-C), 115.44 (2C,10-C and 14-C), 117.36 (8-C),
117.79 (7-C), 118.69 (12-C), 129.17 (11-C), 137.05 (6-C), 137.61 (8a-C), 143.61 (4a-C), 144.65 (9a-C).
Anal. Calcd for C14H13NO2: C, 73.99; H, 5.77; N, 6.16. Found: C, 74.20; H, 5.94; N, 6.33.
N-(4-Chlorophenyl)[1,4]benzodioxin-6-amine (3d)
As described above for 3a but with 1 (1 g, 6.6 mmol) and tris(4-chlorophenyl)bismuth diacetate (3e)

(1.59 g, 2.4 mmol). Purification was performed by chromatography with dichloromethane to yield 0.95 g
1
(32 %) of 3d as brown needles; mp 77°C (from dichloromethane). H-NMR (DMSO-d ) δ: 4.18 (2H, m,
6
2-H), 4.21 (1H, m, 3-H), 6.55 (1H, dd, J = 2.5, 7.8 Hz, 7-H), 6.57 (1H, br s, 5-H), 6.76 (1H, d, J = 8.1 Hz,
13
8-H), 6.91 (2H, d, J = 8.9 Hz, 10-H and 14-H), 7.18 (2H, d, J = 8.9 Hz, 11-H), 8.00 (1H, br s, 9-H). C-
NMR (DMSO-d6) δ: 63.84 (2-C), 64.42 (3-C), 107.63 (5-C), 112.30 (7-C), 116.36 (2C, 10-C and 14-C),
117.37 (8-C), 121.47 (12-C), 128.85 (11-C), 136.24 (6-C), 138.02 (8a-C), 143.57 (4a-C), 143.76 (9a-C).
Anal. Calcd for C14H12NO2Cl: C, 64.25; H, 4.62; N, 5.35. Found: C, 64.31; H, 4.84; N, 5.39.
2-([1,4]Benzodioxin-6-amino)benzoic acid (3e)
A mixture of [1,4]benzodioxin-6-amine (1) (1 g, 6.62 mmol), o-chlorobenzoic acid (2e) (1.5 g, 7.65
mmol), powdered copper (60 mg, 0.9 mmol) and 1-pentanol (30 mL) was heated at 110°C with stirring
for 15 h. The mixture was filtered and the solvent was removed under reduced pressure. Next, ethyl
acetate was added to the residue and the mixture was extracted with sodium hydroxide (100 mL, 0.1 N).
The alkaline layer was acidified with 3N hydrochloric acid until pH = 3 to give 0.95 g (53 %) of 3e as a
1
greenish solid; mp 191°C (from ethanol). H-NMR (DMSO-d ) δ: 4.22 (4H, s, 2-H and 3-H), 6.67 (1H,
6
m, 12-H), 6.72 (1H, d, J = 2.0 Hz, 5-H), 6.72 (1H, dd, J = 1.3, 8.0 Hz, 7-H), 6.84 (1H, d, J = 8.0 Hz, 8-
H), 6.99 (1H, d, J = 8.0 Hz, 10-H), 7.32 (1H, dt, J = 1.3, 7.2 Hz, 11-H), 7.85 (1H, d, J = 7.9 Hz, 13-H).
13
C-NMR (DMSO-d6) δ: 63.96 (2-C), 64.18 (3-C), 111.70 (13a-C), 111.94 (5-C), 113.14 (10-C), 116.51
(12-C), 116.34 (7-C), 117.59 (8-C), 131.80 (13-C), 133.71 (6-C), 134.12 (11-C), 140.10 (8a-C), 143.75
(4a-C), 148.33 (9a-C), 170.06 (COOH). Anal. Calcd for C15H13NO4: C, 66.41; H, 4.83; N, 5.16. Found:
C, 66.23; H, 5.17; N, 5.31.
8-Methyl-11H-[1,4]dioxino[2,3-b]phenothiazine (4a)
A mixture of N-(4-methylphenyl)[1,4]benzodioxin-6-amine (3a) (0.5 g, 2.1 mmol), sulfur (0.13 g, 4.1
mmol) and one crystal of iodine was refluxed under nitrogen in dry o-dichlorobenzene (4 mL) for 6 h.
The mixture was extracted with ether (15 mL), filtered and concentrated. The resulting oil was
chromatographed on silica gel with dichloromethane to yield 0.26 g (47 %) of 4a as a red powder; mp
1
153° C (from dichloromethane). H-NMR (DMSO-d ) δ: 2.12 (3H, s, CH3), 4.13 (2H, m, 2-H), 4.16 (2H,
6
m, 3-H), 6.25 (1H, s, 12-H), 6.47 (1H, s, 5-H), 6.54 (1H, d, J = 8.1 Hz, 10-H), 6.73 (1H, br s, 7-H), 6.78
13
(1H, br d, J = 8.0 Hz, 9-H), 8.21 (1H, s, 11-H). C-NMR (DMSO-d6) δ: 20.00 (CH3), 63.93 (2-C), 64.37
(3-C), 103.03 (12-C), 108.02 (5a-C), 114.19 (5-C), 114.26 (10-C), 116.32 (6a-C), 126.49 (7-C), 127.90
(9-C), 130.25 (8-C), 136.61 (11a-C), 138.31 (4a-C), 139.98 (10a-C), 142.60 (12a-C). Anal. Calcd for
C15H13NO2S: C, 66.40; H, 4.83; N, 5.16. Found: C, 66.72; H, 5.07; N, 5.31.

8-Methoxy-11H-[1,4]dioxino[2,3-b]phenothiazine (4b)
As described above for 4a but with N-(4-methoxyphenyl)[1,4]benzodioxin-6-amine (3b) (0.5 g, 2 mmol)
and sulfur (0.12 g, 4 mmol) gave after chromatography with hexane/ether (70/30) as eluent to yield 0.32
1
g (29 %) of 4b as a yellow powder; mp 152 °C (from ether). H-NMR (DMSO-d ) δ: 3.64 (3H, s, OCH3),
6
4.13 (1H, m, 2-H), 4.16 (1H, m, 3-H), 6.26 (1H, s, 12-H), 6.49 (1H, s, 5-H), 6.58 (2H, m, 9-H and 10-H),
13
6.60 (1H, br s, 7-H), 8.15 (1H, s, 11-H). C-NMR (DMSO-d6) δ: 55.43 (OCH3), 63.92 (2-C), 64.37 (3-
C), 102.95 (12-C), 107.63 (5a-C), 111.58 (7-C), 113.11 (9-C), 114.24 (5-C), 114.96 (10-C), 117.69 (6a-
C), 136.09 (10a-C), 137.12 (11a-C), 138.20 (4a-C), 142.68 (12a-C), 154.33 (8-C). Anal. Calcd for
C15H13NO3S: C, 62.70; H, 4.56; N, 4,87. Found: C, 62.55; H, 4.39; N, 5.14.
11H-[1,4]Dioxino[2,3-b]phenothiazine (4c) and 7H-[1,4]dioxino[2,3-c]phenothiazine (5c)
As described above for 4a but with N-phenyl[1,4]benzodioxin-6-amine (3c) (0.5 g, 2.2 mmol) and sulfur
(0.14 g, 4.4 mmol). After chromatography with ether a mixture (0.32 g, 43 %) of 4c and 5c (60/40) was
obtained.
1
4c, H-NMR (DMSO-d ) δ: 4.14 (H, m, 2-H), 4.17 (2H, m, 3-H), 6.28 (1H, s, 12-H), 6.49 (1H, s, 5-H),
6
6.65 (1H, dd, J = 1.0, 8.0 Hz, 10-H), 6.72 (1H, dt, J = 1.2, 7.4 Hz, 8-H), 6.90 (1H, dd, J = 1.4, 7.7 Hz, 7-
13
H), 6.97 (1H, dt, J = 1.5, 7.4 Hz, 9-H), 8.37 (1H, s, 11-H). C-NMR (DMSO-d6) δ: 63.98 (2-C), 64.41 (3-
C), 103.24 (12-C), 108.09 (5a-C), 114.32 (5-C), 114.37 (10-C), 116.47 (6a-C), 121.42 (8-C), 126.29 (7-
C), 127.50 (9-C), 136.32 (11a-C), 138.58 (4a-C), 142.53 (10a-C), 142.68 (12a-C).
1
5c, H-NMR (DMSO-d ) δ: 4.17 (2H, m, 2-H), 4.23 (2H, m, 3-H), 6.16 (1H, d, J = 8.6 Hz, 6-H), 6.48
6
(1H, d, J = 8.6 Hz, 5-H), 6.58 (1H, dd, J = 1.0, 8.0 Hz, 8-H), 6.68 (1H, dt, J = 1.1, 7.6 Hz, 10-H), 6.86
13
(1H, dd, J = 1.1, 7.7 Hz, 11-H), 6.93 (1H, dt, J = 1.0, 7.8 Hz, 9-H), 8.26 (1H, s, 7-H). C-NMR (DMSO-
d6) δ: 63.70 (3-C), 64.88 (2-C), 105.10 (12a-C), 106.64 (6-C), 114.18 (8-C), 114.91 (5-C), 114.99 (11a-
C), 121.28 (10-C), 126.43 (11-C), 127.65 (9-C), 135.67 (6a-C), 138.27 (4a-C), 139.24 (12b-C), 142.32
(7a-C).
6H-[1,4]Dioxino[2,3-b]acridin-11-one (4e) and 7H-[1,4]dioxino[2,3-a]acridin-12-one (5e)
Polyphosphoric acid procedure: To well stirred polyphosphoric acid (4 g, 1.9 mL), heated to 90 °C, was
added 2-([1,4]benzodioxin-6-amino)benzoic acid (3e) (0.33 g, 1.22 mmol); the mixture was stirred at 110 °C
for 2 h and poured onto ice. The precipitate was collected by filtration, washed with a saturated
solution of sodium hydrogen carbonate and dried to yield a mixture of 4e and 5e (0.22 g, 72 %).
Sulfuric acid procedure: A mixture of 2-([1,4]benzodioxin-6-amino)benzoic acid (3e) (0.33 g, 1.22
mmol) and sulfuric acid (3 mL, 95%) was heated at 80 °C with vigorous stirring for 2 h. Then, ice was
added carefully into the flask. The resulting solution was neutralized with 2N aqueous ammonia. The

precipitate was collected by filtration. The precipitate was washed with water, dried and evaporated to
yield a mixture of 4e and 5e (0.19 g, 62 %). In all cases, the crude reaction product was purified by
chromatography on silica gel. First compound (5e) was eluted with ether and next compound (4e) with
ethanol.
1
5e was obtained as a yellow powder 0.133 g (43 %); mp > 300 °C (from ether). H-NMR (DMSO-d ) δ:
6
4.26 (2H, m, 3-H), 4.33 (2H, m, 2-H), 7.11 (1H, d, J = 8.9 Hz, 6-H), 7.14 (1H, dt, J = 1.4, 7.6 Hz, 10-H),
7.25 (1H, d, J = 9.1 Hz, 5-H), 7.53 (1H, d, J = 7.0 Hz, 8-H), 7.61 (1H, dt, J = 1.3, 7.0 Hz, 9-H), 8.11 (1H,
13
dd, J = 1.4, 7.9 Hz, 11-H), 11.99 (1H, s, 7-H). C-NMR (DMSO-d ) δ: 64.37 (2-C), 63.40 (3-C), 109.11
6
(6-C), 111.82 (12a-C), 116.76 (8-C), 120.46 (10-C), 121.16 (11a-C), 123.90 (5-C), 125.99 (11-C), 132.74
(9-C), 136.09 (4a-C), 137.71 (6a-C), 140.12 (7a-C), 142.82 (12b-C), 176.18 (12-C). Anal. Calcd for
C15H11NO3: C, 71.14; H, 4.38; N, 5.53. Found: C, 71.42; H, 4.68; N, 5.34.
1
4e was obtained as a yellow powder 0.086 g (28 %); mp > 300 °C (from ethanol). H-NMR (DMSO-d )
6
δ: 4.30 (2H, m, 3-H), 4.37 (2H, m, 2-H), 6.93 (1H, s, 12-H), 7.18 (1H, t, J = 7.4 Hz, 8-H), 7.44 (1H, d, J =
8.2 Hz, 10-H), 7.59 (1H, s, 5-H), 7.65 (1H, dt, J = 1.4, 7.6 Hz, 9-H), 8.17 (1H, dd, J = 8.0 Hz, 7-H), 11.46
13
(1H, s, NH). C-NMR (DMSO-d ) δ: 63.91 (3-C), 64.95 (2-C), 102.95 (12-C), 111.78 (5-C), 115.61 (5a-
6
C), 119.58 (5a-C), 120.53 (8-C), 125.98 (7-C), 132.91 (9-C), 136.87 (11a-C), 139.81 (4a-C), 140.91 (10a-
C), 149.46 (12a-C), 176.18 (11-C). Anal. Calcd for C15H11NO3: C, 71.14; H, 4.38; N, 5.53. Found: C,
71.38; H, 4.62; N, 5.29.
11-Chloro[1,4]dioxino[2,3-b]acridine (6a) and 12-chloro[1,4]dioxino[2,3-a]acridine (7a)
A mixture of 2-([1,4]benzodioxin-6-amino)benzoic acid (3e) (0.5 g, 1.85 mmol) and phosphorus
oxychloride (5 mL, 54.6 mmol) was heated at 120°C for 30 min. After cooling, the excess of phosphorus
oxychloride was extracted with petroleum ether (20 mL). The sticky residue was neutralized with 10 %
ammonia. After filtration, the green precipitate was washed with water and dried to yield 0.31 g of 6a
and 7a (62 % yield). The crude reaction product was purified by chromatography on silica gel with
petroleum ether/ether (4/1) to yield two separated fractions. Compound (7a) was obtained from the first
fraction and compound (6a) from the second fraction.
1
7a was obtained as a yellow powder (0.1 g, 20 %); mp 183 °C (from ether). H-NMR (CDCl3) δ: 4.45
(2H, m, 2-H), 4.45 (2H, m, 3-H), 7.41 (1H, d, J = 9.4 Hz, 6-H), 7.58 (1H, td, J = 1.3, 6.6 Hz, 10-H), 7.72
(1H, td, J = 1.4, 7.1 Hz, 9-H), 7.76 (1H, d, J = 9.4 Hz, 5-H), 8.12 (1H, dd, J = 0.7, 7.9 Hz 8-H), 8.50 (1H,
13
dd, J = 1.3, 8.1 Hz, 11-H). C-NMR (CDCl3) δ: 64.02 (3-C), 64.25 (2-C), 118.03 (12a-C), 123.47 (6-C),
124.50 (5-C), 124.71 (11-C), 125.33 (11a-C), 126.91 (10-C), 129.48 (9-C), 129.73 (8-C), 136.12 (12b-C),
137.39 (12-C), 139.29 (4a-C), 146.60 (6a-C), 147.15 (7a-C). Anal. Calcd for C15H10NO2Cl: C, 66.31; H,

3.71; N, 5.16. Found: C, 66.55; H, 3.98; N, 4.86.
1
6a was obtained as a yellow powder 0.160 g (32 %); mp 132°C (from ether). H-NMR (CDCl3) δ: 4.42
(2H, m, 2-H), 4.42 (2H, m, 3-H), 7.53 (1H, td, J = 1.1, 8.0 Hz, 9-H), 7.60 (1H, s, 5-H), 7.70 (1H, td, J =
13
1.4, 8.1 Hz, 8-H), 7.77 (1H, s, 12-H), 8.09 (1H, d, J = 8.6 Hz, 7-H), 8.32 (1H, d, J = 8.5 Hz 10-H). C-
NMR (CDCl3) δ: 64.43 (3-C), 64.49 (2-C), 107.64 (12-C), 112.74 (5-C), 121.43 (11a-C), 123.34 (10a-C),
124.23 (10-C), 125.96 (9-C), 129.15 (7-C), 129.60 (8-C), 136.45 (11-C), 145.61 (12a-C), 146.29 (4a-C),
147.99 (5a-C), 148.61 (6a-C). Anal. Calcd for C15H10NO2Cl: C, 66.31; H, 3.71; N, 5.16. Found: C, 66.60;
H, 3.96; N, 5.41.
N-Butyl[1,4]benzodioxin-6-amine (8a)
To a solution of [1,4]benzodioxin-6-amine (1) (2g, 13.2 mmol) in dry acetonitrile (30 mL) was added 1-
bromobutane (2 g, 14.6 mmol) and sodium hydrogen carbonate (1.23 g, 14.6 mmol). The mixture was
refluxed under stirring for 8 h, neutralized with 2N hydrochloric acid (7 mL), and then dichloromethane
(20 mL) was added. The organic phase was separated, washed twice with water (40 mL), and evaporated.
The residue was dissolved in methanol (20 mL), acidified with sulfuric acid (3 mL), filtrated, and the
filtrate was concentrated to 5 mL volume. The mixture was neutralized with sodium hydrogen carbonate
(1.5 g, 17.9 mmol) and dissolved in dichloromethane (20 mL). The organic phase was separated, washed
twice with water (20 mL) and dried over anhydrous sodium to give a crude reaction product. Purification
1
by chromatography on silica gel with toluene as the eluent gave a yellow oil (8a) (1.4 g, 50 %). H-NMR
(DMSO-d ) δ: 0.89 (3H, t, J = 7.3 Hz, δ-H), 1.35 (2H, m, γ-H), 1.47 (2H, m, β-H), 2.88 (2H, t, J = 7.0 Hz,
6
α-H), 4.08 (2H, m, 2-H), 4.14 (2H, m, 3-H), 5.05 (1H, br s, 9-H), 6.03 (1H, d, J = 2.5 Hz, 5-H), 6.06 (1H,
13
dd, J = 2.6, 8.5 Hz, 7-H), 6.56 (1H, d, J = 8.5 Hz, 8-H). C-NMR (DMSO-d6) δ: 13.95 (δ-C), 19.95 (γ-
C), 31.03 (β-C), 43.30 (α-C), 63.78 (2-C), 64.23 (3-C), 100.23 (5-C), 105.72 (7-C), 117.18 (8-C), 134.15
(8a-C), 143.77 (4a-C), 144.21 (6-C). Anal. Calcd for C12H17NO2: C, 69.54; H: 8.27; N, 6.76. Found: C,
69.87; H: 8.03; N, 6.34.
N-Isopentyl[1,4]benzodioxin-6-amine (8b)
As described above for 8a but with 1 and 1-bromo-3-methylbutane (2.2 g, 14.6 mmol). Work up gave an
1
orange oil (8b) (1.44 g, 48 %). H-NMR (DMSO-d ) δ: 0.89 (6H, t, J = 6.6 Hz, δ-H), 1.39 (2H, dt, J =
6
6.6, 7.3 Hz, β-H), 1.66 (1H, m, γ-H), 2.89 (2H, t, J = 7.2 Hz, α-H), 4.08 (2H, m, 2-H), 4.14 (2H, m, 3-H),
5.04 (1H, br s, 9-H), 6.03 (1H, d, J = 2.6 Hz, 5-H), 6.06 (1H, dd, J = 2.6, 8.6 Hz, 7-H), 6.57 (1H, d, J =
13
8.5 Hz, 8-H). C-NMR (DMSO-d6) δ: 22.61 (δ-C), 25.46 (γ-C), 37.91 (β-C), 41.77 (α-C), 63.77 (2-C),
64.41 (3-C), 100.23 (5-C), 105.72 (7-C), 117.17 (8-C), 134.16 (8a-C), 143.75 (4a-C), 144.21 (6-C). Anal.

Calcd for C13H19NO2: C,70.56; H, 8.65; N, 6.33. Found: C,70.94; H, 8.43; N, 6.56.
N-Isopropyl[1,4]benzodioxin-6-amine (8c)
As described above for 8a but with 1, 2-bromopropane (1.8 g, 14.6 mmol) and sodium hydrogen
carbonate (2 g, 23.8 mmol). Next, the solution was refluxed under stirring for 72 h. After work up a
1
yellow oil (8c) was obtained (1 g, 40 %). H-NMR (DMSO-d ) δ: 1.07 (6H, d, J = 6.3 Hz, β-C), 3.38 (1H,
6
m, α-C), 4.08 (2H, m, 2-H), 4.14 (2H, m, 3-H), 4.85 (1H, s, 9-H), 6.05 (1H, d, J = 2.0 Hz, 5-H), 6.06 (1H,
13
dd, J = 2.0, 8.1 Hz, 7-H), 6.56 (1H, d, J = 7.9 Hz, 8-H). C-NMR (DMSO-d6) δ: 22.61 (β-C), 43.71 (α-
C), 63.78 (2-C), 64.14 (3-C), 101.03 (5-C),106.38 (7-C), 117.22 (8-C), 134.13 (8a-C), 143.12 (6-C),
143.78 (4a-C). Anal. Calcd for C11H15NO2: C, 68.37; H, 7.82; N, 7.25. Found: C, 68.51; H, 7.74; N, 7.52.
N-(1-Methylbutyl)[1,4]benzodioxin-6-amine (8d)
As described above for 8a but with 1 and 2-bromopentane (2.2 g, 14.6 mmol). After work up a white oil
1
(8d) was obtained (1.55 g, 53 %). H-NMR (DMSO-d ) δ: 0.86 (3H, t, J = 7.1 Hz, δ-H), 1.03 (3H, d, J =
6
6.3 Hz, α'-H), 1.32 (2H, m, γ- H ), 1.44 (2H, m, β-H), 3.23 (1H, m, α-H), 4.08 (2H, m, 2-H), 4.14 (2H, m,
3-H), 4.84 (1H, s, 9-H), 6.03 (1H, d, J = 2.6 Hz, 5-H), 6.05 (1H, dd, J = 2.6, 8.3 Hz, 7-H), 6.55 (1H, d, J =
13
8.4 Hz, 8-H). C-NMR (DMSO-d6) δ: 14.16 (δ-C), 18.98 (γ-C), 20.49 (α'-C), 38.70 (β-C), 47.67 (α-C),
63.78 (2-C), 64.22 (3-C), 100.71 (5-C), 106.12 (7-C), 117.22 (8-C), 133.94 (8a-C), 143.42 (6-C), 143.78
(4a-C). Anal. Calcd for C13H19NO2: C, 70.56; H, 8.65; N, 6.33. Found: C, 70.82; H, 8.33; N, 6.58.
N-Butyl-N-phenyl[1,4]benzodioxin-6-amine (9a)
To a solution of N-butyl[1,4]benzodioxin-6-amine (8a) (1 g, 4.8 mmol) in dry dichloromethane (30 mL)
at rt were slowly added triphenylbismuth diacetate (2c) (0.9 g, 1.6 mmol) and copper(II) acetate (0.09 g,
0.48 mmol). The mixture was stirred at rt for 4 h. Next, dichloromethane (20mL) was added, and the
resulting mixture was filtered. The insoluble part was washed with dichloromethane (2 x 20 mL), and the
organic layers were dried over anhydrous sodium sulphate and evaporated to give a crude reaction
product, which was purified by chromatography on silica gel with toluene as the eluent. A yellow oil was
1
recovered, yielding 0.20 g (15 %) of 9a. H-NMR (DMSO-d ) δ: 0.86 (3H, t, J = 7.3 Hz, δ-H), 1.30 (2H,
6
m, α-H), 1.50 (2H, m, β-H), 3.55 (2H, t, J = 7.5 Hz, γ-H), 4.22 (4H, s, 2-H and 3-H), 6.55 (1H, dd, J = 2.6,
8.3 Hz, 7-H), 6.57 (1H, d, J = 2.5 Hz, 5-H), 6.70 (1H, m, 12-H), 6.72 (2H, m, 10-H), 6.82 (1H, d, J = 8.3
13
Hz, 8-H), 7.13 (2H, m, 11-H). C-NMR (DMSO-d6) δ: 13.87 (δ-C), 19.68 (γ-C), 29.16 (β-C), 51.40 (α-
C), 63.97 (2-C), 64.14 (3-C), 113.47 (5-C), 116.27 (2C, 10-C and 14-C), 117.69 (8-C), 117.96 (7-C),
118.23 (12-C), 128.99 (2C, 11-C and 13-C), 139.93 (8a-C), 140.88 (6-C), 143.81 (4a-C), 148.83 (9a-C).

Anal. Calcd for C18H21NO2: C, 76.29; H, 7.47; N, 4.94. Found: C, 76.36; H, 7.61; N, 4.77.
N-Butyl-N-(4-methoxyphenyl)[1,4]benzodioxin-6-amine (9b)
As described above for 9a but with N-butyl[1,4]benzodioxin-6-amine (8a) (1 g, 4.8 mmol) and 4-
methoxyphenyllead triacetate (2b) (2.6 g, 5.3 mmol). Chromatography yielded a brown oil (0.45 g, 30 %)
1
of 9b. H-NMR (DMSO-d ) δ: 0.86 (3H, t, J = 7.3 Hz, δ-H), 1.30 (2H, m, γ-H), 1.47 (2H, m, β-H), 3.49
6
(2H, t, J = 7.5 Hz, α-H), 3.71 (3H, s, OCH3), 4.16 (4H, br s, 2-H and 3-H), 6.26 (1H, d, J = 2.7 Hz, 5-H),
6.28 (1H, dd, J = 2.7, 8.2 Hz, 7-H), 6.69 (1H, d, J = 8.1 Hz, 8-H), 6.86 (2H, d, J = 8.9 Hz, 11-H and 13-
13
H), 6.90 (2H, d, J = 8.9 Hz, 10-H and 14-H). C-NMR (DMSO-d6) δ: 13.93 (δ-C), 19.74 (γ-C), 29.33 (β-
C), 51.77 (α-C), 55.30 (OCH3), 63.92 (2-C), 64.34 (3-C), 107.38 (5-C), 112.02 (7-C), 114.76 (2C, 11-C
and 13-C), 117.30 (8-C), 123.90 (2C, 10-C and 14-C), 137.10 (8a-C), 141.38 (9a-C), 143.12 (6-C),
143.59 (4a-C), 154.66 (12-C). Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 72.69;
H, 7.23; N, 4.55.
N-Butyl-N-(4-methylphenyl)[1,4]benzodioxin-6-amine (9c)
As described above for 9a but with N-butyl[1,4]benzodioxin-6-amine (8a) (1 g, 4.8 mmol) and p-
1
tolyllead triacetate (2a) (2.5 g, 5.3 mmol). Chromatography yielded a brown oil (0.40 g, 26 %) of 9c. H-
NMR (DMSO-d ) δ: 0.86 (3H, t, J = 7.3 Hz, δ-H), 1.30 (2H, m, γ-H), 1.48 (2H, m, β-H), 2.19 (3H, s,
6
CH3), 3.52 (2H, t, J = 7.5 Hz, α-H), 4.20 (4H, br s, 2-H and 3-H), 6.44 (1H, dd, J = 2.7, 8.2 Hz, 7-H), 6.46
(1H, d, J = 2.7 Hz, 5-H), 6.71 (2H, d, J = 8.6 Hz, 10-H), 6.76 (1H, d, J = 8.2 Hz, 8-H), 6.99 (2H, d, J = 8.6
13
Hz, 11-H and 13-H). C-NMR (DMSO-d6) δ: 13.91 (δ-C), 19.72 (γ-C), 20.21 (CH3), 29.26 (β-C), 51.52
(α-C), 63.96 (2-C), 64.24 (3-C), 111.24 (5-C), 115.81 (7-C), 117.51 (8-C), 118.63 (2C, 10-C and 14-C),
128.33 (12-C), 129.62 (2C, 11-C and 13-C), 138.82 (8a-C), 141.82 (6-C), 143.70 (4a-C), 146.01 (9a-C).
Anal. Calcd for C19H23NO2: C, 76.73; H: 7.80; N, 4.71. Found: C, 76.41; H: 7.91; N, 5.02.
N-Isopentyl-N-phenyl[1,4]benzodioxin-6-amine (9d)
As described above for 9a but with N-isopentyl[1,4]benzodioxin-6-amine (8b) (1 g, 4.5 mmol) and
triphenylbismuth diacetate (2c) (0.9 g, 1.6 mmol). Chromatography yielded an orange oil (9d) (0.50 g, 35
1
%). H-NMR (DMSO-d ) δ: 0.87 (6H, d, J = 6.8 Hz, δ-H), 1.43 (2H, dt, J = 6.8, 7.8 Hz, β-H), 1.60 (1H,
6
m, γ-H), 3.57 (2H, t, J = 7.8 Hz, α-H), 4.22 (4H, s, 2-H and 3-H), 6.55 (1H, dd, J = 2.0, 8.0 Hz, 7-H), 6.56
(1H, d, J = 2.0 Hz, 5-H), 6.70 (2H, m, 10-H and 14-H), 6.71 (1H, m, 12-H), 6.83 (1H, d, J = 8.0 Hz, 8-H),
13
7.14 (2H, m, 11-H and 13-H). C-NMR (DMSO-d6) δ: 22.59 (δ-C), 25.71 (α-C), 35.77 (β-C), 50.13 (α-
C), 64.01 (2-C), 64.22 (3-C), 113.45 (5-C), 116.29 (2C, 10-C and 14-C), 117.76 (7-C), 117.96 (8-C),
118.31 (12-C), 129.08 (2C, 11-C and 13-C), 139.97 (8a-C), 140.91 (6-C), 143.86 (4a-C), 148.40 (9a-C).

Anal. Calcd for C19H23NO2: C, 76.73; H, 7.80; N, 4.71. Found: C, 76.41; H, 7.97; N, 4.36.
N-Isopropyl-N-phenyl[1,4]benzodioxin-6-amine (9e)
As described above for 9a but with N-isopropyl[1,4]benzodioxin-6-amine (8c) (1 g, 5.2 mmol) and
triphenylbismuth diacetate (2c) (1 g, 1.8 mmol). Chromatography yielded a yellow oil (9e) (0.63 g, 45
1
%). H-NMR (DMSO-d ) δ: 1.05 (6H, d, J = 6.5 Hz, β-H), 4.23 (1H, m, α-H), 4.24 (4H, s, 2-H and 3-H),
6
6.48 (1H, dd, J = 2.5, 8.2 Hz, 7-H), 6.50 (1H, d, J = 2.5 Hz, 5-H), 6.55 (2H, m, 10-H and 14-H), 6.66 (1H,
13
m, 12-H), 6.87 (1H, d, J = 8.1 Hz, 8-H), 7.11 (2H, m, 11-H and 13-H). C-NMR (DMSO-d6) δ: 20.74 (β-
C), 47.06 (α-C), 64.04 (2-C), 64.12 (3-C), 115.84 (2C, 10-C and 14-C), 117.51 (8-C), 117.57 (2C, 5-C
and 7-C), 121.94 (12-C), 128.92 (2C, 11-C and 13-C), 136.67 (8a-C), 141.26 (6-C), 143.72 (4a-C),
148.41 (9a-C). Anal. Calcd for C17H19NO2: C, 75.81; H, 7.11; N, 5.20. Found: C, 76.03; H, 6.94; N, 5.49.
N-(1-Methylbutyl)-N-(4-methylphenyl)[1,4]benzodioxin-6-amine (9f)
As described above for 9a but with N-(1-methylbutyl)[1,4]benzodioxin-6-amine (8d) (1 g, 4.48 mmol)
and p-tolyllead triacetate (2a) (2.34 g, 4.94 mmol). Chromatography yielded a brown oil (9f) (0.24 g, 17
1
%). H-NMR (DMSO-d ) δ: 0.86 (3H, t, J = 7.3 Hz, δ-H), 1.04 (3H, d, J = 6.5 Hz, α'-H), 1.34 (2H, m, g-
6
H), 1.51 (2H, m, β-H), 2.18 (3H, s, CH3), 3.98 (1H, m, α-H), 4.21 (4H, s, 2-H and 3-H), 6.34 (1H, d, J =
2.5 Hz, 5-H), 6.35 (1H, dd, J = 2.5, 8.2 Hz, 7-H), 6.57 (2H, d, J = 8.5 Hz, 10-H and 14-H), 6.76 (1H, d, J
13
= 8.2 Hz, 8-H), 6.99 (2H, d, J = 8.5 Hz, 11-H and 13-H). C-NMR (DMSO-d6) δ: 14.10 (δ-C), 18.61 (γ-
C), 19.70 (α'-C), 20.17 (CH3), 37.21 (β-C), 51.99 (α-C), 63.98 (2-C), 64.18 (3-C), 113.91 (5-C), 117.34
(8-C), 118.44 (7-C), 119.56 (10-C), 128.30 (12-C), 129.53 (11-C), 139.21 (8a-C), 139.56 (6-C), 143.57
(4a-C), 145.34 (9a-C). Anal. Calcd for C20H25NO2: C, 77.14; H: 8.09; N, 4.50. Found C, 77.55; H, 7.82;
N, 4.37.
N-(1-Methylbutyl)-N-phenyl[1,4]benzodioxin-6-amine (9g)
As described above for 9a but with N-(1-methylbutyl)[1,4]benzodioxin-6-amine (8d) (1 g, 4.48 mmol)
and triphenylbismuth diacetate (2d) (0.9 g, 1.6 mmol). Chromatography yielded an orange oil (9g) (0.44
1
g, 33 %). H-NMR (DMSO-d ) δ: 0.87 (3H, t, J = 7.4 Hz, δ-H),1.06 (3H, d, J = 6.5 Hz, α-H), 1.36 (2H,
6
m, γ-H), 1.52 (2H, m, β-H), 4.04 (1H, m, α-H), 4.24 (4H, s, 2-H and 3-H), 6.48 (1H, dd, J = 2.3, 8.3 Hz,
7-H), 6.50 (1H, d, J = 2.3 Hz, 5-H), 6.56 (2H, m, 10-H and 14-H), 6.66 (1H, m, 12-H), 7.11 (2H, m, 11-H
13
and 13-H). C-NMR (DMSO-d6) δ: 13.91 (δ-C), 18.47 (γ-C), 19.53 (α'-C), 37.01 (β-C), 51.68 (α-C),
63.89 (2-C), 63.98 (3-C), 116.01 (2C, 10-C and 14-C), 116.93 (5-C), 117.38 (7-C), 117.54 (8-C), 121.41
(12-C), 128.75 (2C, 11-C and 13-C), 137.02 (8a-C), 140.93 (6-C), 143.56 (4a-C), 148.57 (9a-C). Anal.

Calcd for C19H23NO2: C, 76.73; H: 7.80; N, 4.71. Found: C, 76.92; H: 7.87; N, 4.65.
11-Butyl-11H-[1,4]dioxino[2,3-b]phenothiazine (10a)
A mixture of 9a (0.20 g, 0.7 mmol), sulfur (0.05 g, 1.4 mmol), and one crystal of iodine in dry o-
dichlorobenzene (2 mL) was refluxed under nitrogen for 8 h. The mixture was extracted with ether (10
mL), filtered and concentrated. The resulting oil was added on silicagel (5 g), and the mixture was
washed with hexane (250 mL) to eliminate o-dichlorobenzene excess. Then the resulting silicagel/10a
mixture was washed with ether (250 mL); the organic phase was dried over anhydrous sodium sulphate
and evaporated to yield an oil. This oil was diluted with light petroleum (30 mL) and kept for one night at
1
4°C to afford a viscous green precipitate of 10a after filtration (0.033 g, 15%). H-NMR (DMSO-d ) δ:
6
0.86 (3H, t, J = 7.4 Hz, δ-H), 1.36 (2H, m, γ-H), 1.62 (2H, m, β-H), 3.76 (2H, t, J = 6.8 Hz, α-H), 4.16
(2H, m, 3-H), 4.20 (2H, m, 2-H), 6.53 (1H, s, 12-H), 6.67 (1H, t, 5-H), 6.89 (1H, t, J = 7.4 Hz, 8-H), 6.96
13
(1H, d, J = 8.2 Hz, 10-H), 7.11 (1H, d, J = 7.6 Hz, 7-H), 7.16 (1H, t, J = 7.9 Hz, 9-H). C-NMR
(DMSO-d6) δ: 13.67 (δ-C), 19.46 (γ-C), 28.47 (β-C), 46.25 (α-C), 63.97 (3-C), 64.32 (2-C), 105.07 (12-
C), 114.98 (5-C), 115.30 (5a-C), 115.64 (10-C), 122.02 (8-C), 123.97 (6a-C), 127.05 (7-C), 127.46 (9-C),
138.86 (4a-C), 138.99 (11a-C), 142.78 (12a-C), 145.21 (10a-C). Anal. Calcd for C18H19NO2S: C, 68.98;
H, 6.11; N, 4.47. Found: C, 69.05; H, 5.87; N, 4.62.
11-Butyl-8-methoxy-11H-[1,4]dioxino[2,3-b]phenothiazine (10b)
As described above for 10a but with N-butyl-N-(4-methoxyphenyl)[1,4]benzodioxin-6-amine (9b) (0.4 g,
1
1.3 mmol). Work up yielded 0.075 g (17 %) of 10b as a green oil. H-NMR (DMSO-d ) δ: 0.85 (3H, t, J
6
= 7.3 Hz, δ-H), 1.35 (2H, m, γ-H), 1.60 (2H, m, β-H), 3.71 (2H, t, J = 6.8 Hz, α-H), 3.68 (3H, s, OCH3),
4.16 (2H, m, 3-H), 4.20 (2H, m, 2-H), 6.50 (1H, s, 12-H), 6.66 (1H, s, 5-H), 6.77 (1H, dd, J = 1.2, 8.0 Hz,
13
9-H), 6.80 (1H, d, J = 1.1 Hz, 7-H), 6.88 (1H, d, J = 7.5 Hz, 10-H). C-NMR (DMSO-d6) δ: 13.70 (δ-C),
19.48 (α-C), 28.55 (β-C), 46.39 (γ-C), 55.49 (OCH3), 63.98 (3-C), 64.36 (2-C), 104.78 (12-C), 112.44 (7-
C), 112.89 (9-C), 114.97 (5-C), 115.08 (5a-C), 116.36 (10-C), 125.54 (6a-C), 138.54 (2C, 4a and 10a-C),
138.54 (4a-C), 139.75 (11a-C), 142.82 (12a-C), 154.63 (8-C). Anal. Calcd for C19H21NO3S: C, 66.45; H,
6.16; N, 4.08. Found: C, 66.69; H, 6.34; N, 4.27.
11-Isopentyl-11H-[1,4]dioxino[2,3-b]phenothiazine (10d)
As described above for 10a but with N-isopentyl-N-phenyl[1,4]benzodioxin-6-amine (9d) (0.5 g, 1.7
1
mmol). Work up yielded a green oil (10d) (0.06 g, 11 %). H-NMR (DMSO-d ) δ: 0.87 (6H, d, J = 6.6
6
Hz, δ-H), 1.54 (2H, q, J = 6.9 Hz, β-H), 1.69 (1H, m, γ-H), 3.77 (1H, t, J = 7.0 Hz, α-H), 4.16 (2H, m, 3-
H), 4.19 (2H, m, 2-H), 6.54 (1H, s, 12-H), 6.67 (1H, s, 5-H), 6.88 (1H, t, J = 7.5 Hz, 8-H), 6.96 (1H, d, J =

13
8.2 Hz, 10-H), 7.11 (1H, d, J = 7.7 Hz, 7-H), 7.16 (1H, t, J = 7.8 Hz, 9-H). C-NMR (DMSO-d6) δ: 22.41
(δ-C), 25.58 (γ-C), 35.33 (β-C), 44.97 (α-C), 63.97 (3-C), 64.33 (2-C), 105.04 (12-C), 115.01 (5-C),
115.35 (5a-C), 115.61 (10-C), 122.03 (8-C), 124.05 (6a-C), 127.06 (7-C), 127.45 (9-C), 138.87 (4a-C),
139.04 (11a-C), 142.79 (12a-C), 145.22 (10a-C). Anal. Calcd for C19H21NO2S: C, 69.69; H, 6.46; N, 4.28.
Found: C, 69.21; H, 6.09; N, 4.53.
2-Diethylamino-1-(8-methyl-11H-[1,4]dioxino[2,3-b]phenothiazin-11-yl)ethan-1-one (11a)
To a solution of 8-methyl-11H-[1,4]dioxino[2,3-b]phenothiazine (4a) (0.19 g, 0.7 mmol) in toluene (7
mL) was added chloroacetyl chloride (0.057 g, 0.5 mmol), and the mixture was kept at 35 °C under
stirring for 45 min. The solution was concentrated, and to the residual viscous oil a solution of N,N-
diethylamine (2 mL) in toluene (4 mL) was added. The solution was refluxed for 2 h under stirring and
evaporated to yield a crude reaction product which was purified by chromatography on silica gel with
1
toluene as the eluent. A red oil was obtained (11a) (0.14 g, 52 %). H-NMR (DMSO-d ) δ: 0.81 (6H, t, J
6
= 7.1 Hz, δ-H), 2.45 (4H, q, J = 7.1 Hz, γ-H), 2.30 (3H, s, CH3), 3.40 (2H, br s, β-H), 4.25 (4H, m, 2-H
and 3-H), 6.99 (1H, s, 5-H), 7.14 (1H, s, 12-H), 7.17 (1H, br d, J = 8.0 Hz, 9-H), 7.31 (1H, br s, 7-H), 7.45
13
(1H, d, J = 8.0 Hz, 10-H). C-NMR (DMSO-d6) δ: 12.11 (δ-C), 20.45 (CH3), 46.81 (γ-C), 54.63 (β-C),
64.23 (2-C), 64.27 (3-C), 115.26 (5-C), 115.83 (12-C), 123.77 (5a-C), 126.78 (7-C), 127.71 (10-C),
127.93 (9-C), 132.27 (6a-C), 132.35 (11a-C), 136.40 (8-C), 136.50 (10a-C), 142.10 (4a-C), 142.49 (12a-
C), 169.26 (CO). Anal. Calcd for C21H24N2O3S: C, 65.60; H, 6.29; N, 7.29. Found: C, 65.41; H, 6.53; N,
7.60.
2-Diethylamino-1-(8-methoxy-11H-[1,4]dioxino[2,3-b]phenothiazin-11-yl)ethan-1-one (11b)
As described above for 11a but with 8-methoxy-11H-[1,4]dioxino[2,3-b]phenothiazine (4b) (0.2 g, 0.7
1
mmol). After work up, a green oil (11b) (0.17 g, 61 %) was obtained. H-NMR (DMSO-d ) δ: 0.80 (6H,
6
t, J = 7.1 Hz, δ-H), 2.43 (4H, q, J = 7.1 Hz, γ-H), 3.25 (2H, s, β-H), 3.76 (3H, s, OCH3), 4.22 (2H, m, 3-
H), 4.26 (2H, m, 2-H), 6.90 (1H, dd, J = 2.8, 8.8 Hz, 9-H), 7.02 (1H, s, 5-H), 7.08 (1H, d, J = 2.6 Hz, 7-
13
H), 7.18 (1H, s, 12-H), 7.47 (1H, br d, J = 8.8 Hz, 10-H). C-NMR (DMSO-d6) δ: 12.13 (δ-C), 46.80 (γ-
C), 54.42 (β-C), 55.72 (OCH3), 64.18 (3-C), 64.22 (2-C), 112.28 (7-C), 113.18 (9-C), 115.29 (5-C),
115.81 (12-C), 123.80 (5a-C), 127.79 (10-C), 131.71 (10a-C), 132.44 (11a-C), 133.85 (6a-C), 142.01 (4a-
C), 142.48 (12a-C), 157.49 (8-C), 169.34 (CO). Anal. Calcd for C21H24N2O4S: C, 62.98; H, 6.04; N, 6.99.
Found: C, 63.17; H, 5.95; N, 6.87.
2-Diethylamino-1-(8-methoxy-11H-[1,4]dioxino[2,3-b]phenothiazin-11-yl)ethan-1-one (11c)
As described above for 11a but with 11H-[1,4]dioxino[2,3-b]phenothiazine (4c) (0.18 g, 0.7 mmol). After

1
work up, a green oil (11c) (0.18 g, 69 %) was obtained. H-NMR (DMSO-d ) δ: 0.83 (6H, t, J = 7.0 Hz,
6
δ-H), 2.43 (4H, q, J = 7.1 Hz, γ-H), 3.38 (2H, s, β-H), 4.24 (4H, m, 2-H and 3-H), 7.01 (1H, s, 5-H), 7.16
(1H, s, 12-H), 7.28 (1H, t, J = 7.8 Hz, 9-H), 7.39 (1H, dt, J = 1.2, 7.8 Hz, 8-H), 7.53 (1H, dd, J = 1.0, 8.0
13
Hz, 7-H), 7.57 (1H, d, J = 8.1 Hz, 10-H). C-NMR (DMSO-d6) δ: 12.11 (δ-C), 46.83 (γ-C), 54.61 (β-C),
64.20 (3-C), 64.25 (2-C), 115.28 (5-C), 115.80 (12-C), 123.78 (5a-C), 126.71 (7-C), 127.39 (8-C), 127.44
(9-C), 127.70 (10-C), 132.38 (11a-C), 132.75 (6a-C), 138.95 (10a-C), 142.08 (4a-C), 142.48 (12a-C),
169.38 (CO). Anal. Calcd for C20H22N2O3S: C, 64.84; H, 5.99; N, 7.56. Found: C, 64.65; H, 6.30; N, 7.76.
6-Methyl-6H-[1,4]dioxino[2,3-b]acridin-11-one (12a) and 7-methyl-7H-[1,4]dioxino[2,3-a]acridin-
12-one (13a)
A mixture of 4e and 5e (0.5 g, 1.97 mmol), potassium hydroxide (0.5 g, 8.9 mmol), water (5 mL) and
acetone (40 mL) was heated at 80 °C for 15 min. A solution of dimethyl sulfate (0.2 mL, 3.2 mmol) in
acetone (10 mL) was added dropwise. The reacting mixture was heated for 2 h more and concentrated to
10 mL volume. After cooling, the precipitate was recovered (0.4 g, 77 %). This crude reaction product
was purified by chromatography on silica gel with ether to yield two separated fractions. Compound
(12a) was obtained from the first fraction and compound (13a) from the second one.
1
12a was obtained as a yellow powder (0.15 g, 28 %); mp 247 °C (from ether). H-NMR (CDCl3) δ: 3.74
(3H, s, CH3), 4.28 (2H, m, 2-H), 4.36 (2H, m, 3-H), 6.90 (1H, s, 5-H), 7.20 (1H, dt, J = 0.6, 7.1 Hz, 9-H),
7.40 (1H, d, J = 8.0 Hz, 7-H), 7.63 (1H, dt, J = 1.7, 6.9 Hz, 8-H), 7.97 (1H, s, 12-H), 8.48 (1H, dd, J =1.7,
13
8.0 Hz, 10-H). C-NMR (CDCl3) δ: 33.66 (CH3), 63.99 (2-C), 65.06 (3-C), 102.00 (5-C), 114.27 (12-C),
114.33 (7-C), 117.56 (11a-C), 120.65 (9-C), 121.69 (10a-C), 127.60 (10-C), 133.13 (8-C), 138.69 (5a-C),
139.56 (12a-C), 142.38 (6a-C), 149.50 (4a-C), 176.73 (11-C). Anal. Calcd for C16H13NO3: C, 71.90; H,
4.90; N, 5.24. Found C, 72.19; H, 4.67; N, 5.57.
1
13a was obtained as a yellow powder (0.23 g, 43 %); mp 175 °C (from ether). H-NMR (CDCl3) δ: 3.60
(3H, s, CH3), 4.32 (2H, m, 2-H), 4.48 (2H, m, 3-H), 6.96 (1H, d, J = 9.4 Hz, 6-H), 7.22 (1H, dt, J = 1.6,
7.1 Hz, 10-H), 7.25 (1H, d, J = 9.3 Hz, 5-H), 7.40 (1H, d, J = 8.6 Hz, 8-H), 7.64 (1H, dt, J = 1.7, 6.9 Hz,
13
9-H), 8.48 (1H, dd, J = 1.5, 8.5 Hz, 11-H). C-NMR (CDCl3) δ: 33.44 (CH3), 63.69 (3-C), 64.95 (2-C),
106.72 (6-C), 113.88 (12a-C), 114.07 (8-C), 120.85 (10-C), 123.30 (5-C), 123.64 (11a-C), 127.79 (11-C),
133.12 (9-C), 137.05 (4a-C), 139.40 (6a-C), 141.82 (7a-C), 144.06 (12b-C), 177.81 (12-C). Anal. Calcd
for C16H13NO3: C, 71.90; H, 4.90; N, 5.24. Found C, 71.80; H, 5.26; N, 5.61.
6-[2-(Dimethylamino)ethyl]-6H-[1,4]dioxino[2,3-b]acridin-11-one (14a) and 7-[2-(dimethyl-
amino)ethyl]-7H-[1,4]dioxino[2,3-a]acridin-12-one (15a).
A mixture of 4e and 5e (0.3 g, 1.18 mmol) and 50 % sodium hydroxide (9 mL, 0.11 mol) was warmed

until dissolution. Next triethylbenzylammonium chloride (0.14 g, 1 mmol), 2-(dimethylamino)ethyl
chloride hydrochloride (0.4 g, 2.8 mmol) and toluene (20 mL) were added. The resulting mixture was
heated under stirring at 100°C for 4 days. After cooling the organic phase was recovered, washed with
water, dried over anhydrous magnesium sulphate, and evaporated to yield a brown oil (0.077 g, 20 %).
This crude reaction product was purified by chromatography on silica gel, with ether/ethanol (1/1) to
yield two separated fractions. Compound (14a) was obtained from the first fraction and 15a from the
second fraction.
1
14a was obtained as a yellow powder (0.031 g, 8 %); mp 130 °C (from ether). H-NMR (DMSO-d ) δ:
6
2.27 (6H, s, γ-H), 2.61 (2H, t, J = 6.9 Hz, β-H), 4.35 (4H, m, 2-H and 3-H), 4.45 (2H, m, α-H), 7.16 (1H,
s, 5-H), 7.26 (1H, t, J = 6.9 Hz, 9-H), 7.66 (1H, d, J = 8.0 Hz, 7-H), 7.69 (1H, s, 12-H), 7.76 (1H, t, J =
13
6.7 Hz, 8-H), 8.27 (1H, d, J = 7.9 Hz, 10-H). C-NMR (DMSO-d6) δ: 44.31 (β-C), 45.70 (γ-C), 55.65 (α-
C), 63.86 (2-C), 64.90 (3-C), 102.59 (5-C), 112.55 (12-C), 115.43 (7-C), 116.53 (11a-C), 120.76 (9-C),
120.76 (10a-C), 126.55 (10-C), 133.64 (8-C), 137.54 (5a-C), 139.60 (12a-C), 141.47 (6a-C), 149.65 (4a-
C), 175.01 (11-C). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found: C, 70.58; H, 6.48; N,
8.29.
1
15a was obtained as a yellow powder (0.030 g, 8 %); mp 202 °C (from ether). H-NMR (DMSO-d ) δ:
6
2.29 (6H, s, γ-H), 2.65 (2H, t, J = 6.9 Hz, β-H), 4.31 (4H, m, 2-H and 3-H), 4.44 (2H, m, α-H), 7.17 (1H,
d, J = 9.2 Hz, 6-H), 7.23 (1H, t, J = 7.3 Hz, 10-H), 7.34 (1H, d, J = 9.4 Hz, 5-H), 7.66 (1H, d, J = 7.2 Hz,
13
8-H), 7.75 (1H, t, J = 7.5 Hz, 9-H), 8.19 (1H, d, J = 8.0 Hz, 11-H). C-NMR (DMSO-d6) δ: 44.75 (β-C),
45.58 (γ-C), 55.69 (α-C), 63.37 (2-C), 64.35 (3-C), 107.26 (6-C), 113.08 (12a-C), 115.17 (8-C), 120.81
(10-C), 122.68 (11a-C), 123.64 (5-C), 126.65 (11-C), 133.57 (9-C), 136.71 (4a-C), 138.01 (6a-C), 140.82
(7a-C), 143.57 (12b-C), 175.83 (12-C). Anal. Calcd for C19H20N2O3: C, 70.35; H, 6.21; N, 8.64. Found:
C, 70.02; H, 6.43; N, 8.95.
REFERENCES
1. R. M. Acheson, 'Acridines', Wiley, New York, 1973.
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Gupta. Elsevier, 1988.
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P. W. Groundwater and M. A. Munawar, Advances in Heterocyclic Chemistry, Vol. 70, ed. by A.R.
Katrizky and A. J. Boulton, Academic Press, London, 1998, p. 89-161.
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Elguero, and J. Barbe, J. Chem. Res. 1990, (S) 350, (M) 2601.
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Manian, J. Heterocycl. Chem., 1976, 13, 1067.
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