A cleavage reaction of benzothiazole with cyclic 1,3-dicarbonyls in the presence of potassium dihydrogen phosphate

Article abstract of DOI:10.3184/174751915X14449331711796

A facile and convenient synthesis of phenothiazine derivatives has been achieved by condensation reaction of benzothiazole derivatives with 1,3-dicarbonyls in the presence of potassium dihydrogen phosphate (KH2PO4) in moderate to good yields under mild conditions.

Full text of DOI:10.3184/174751915X14449331711796

JOURNAL OF CHEMICAL RESEARCH 2015
VOL. 39 NOVEMBER, 657–660
RESEARCH PAPER 657
A cleavage reaction of benzothiazole with cyclic 1,3-dicarbonyls in the
presence of potassium dihydrogen phosphate
a
a
b
a
Ayman Mohammed Yousif Suliman , Yanjun Li , Shaonan Zhang and Yu Yuan *
a
College of Chemistry & Chemical Engineering, Yangzhou University, Jiangsu Province 225002, P. R. China
No.1 Oil Production Plant of Changqing Oil Field, CNPC, Shanxi Province 710600, P. R. China
b
A facile and convenient synthesis of phenothiazine derivatives has been achieved by condensation reaction of benzothiazole derivatives
with 1,3-dicarbonyls in the presence of potassium dihydrogen phosphate (KH PO ) in moderate to good yields under mild conditions.
2
4
Keywords: potassium dihydrogen phosphate, benzothiazoles, 1,3-dicarbonyls, phenothiazines, cleavage reaction
Phenothiazine derivatives exhibit a variety of biological
entry 1). Only a modest yield 15% was obtained under these
1-9
activities and are widely used in medicine. These compounds
possess a wide spectrum of biological and pharmacological
activities due to the presence of nitrogen and sulfur groups,
which are considered to be one of the structural features that
conditions. Interestingly, when potassium phosphate was
changed to sodium acetate, the reaction result was enhanced
(50% yield) (Table 1, entry 2). However, neither alkali nor
organic bases could enhance the reactivity of this reaction
10-13
impart their activities.
Modifications of the phenothiazine
(
Table 1, entries 2–5). It seems that the base had less effect on
ring system produce different activities, such as neuroleptics,
tranquilisers, antihistaminic, anticholinergic, anthelmintic,
antibacterial and antiallergics.
The synthesis of potential drug-delivery systems from
maleic anhydride copolymers and phenothiazine derivatives
a
Table 1 Screening of optimal conditions in the formation of 3b
H
N
14-21
N
O
O
Solvent, Additive
Air, 80°C, 3 days
+
S
S
O
2
2,23
24
has been reported.
in-situ synthesis of 1,4-benzothiazines without solvent from
-aminobenzenethiol and acyclic 1,3-dicarbonyls under
oxidative conditions involving the formation of dimer of
Munde and coworkers reported an
1a
2b
3b
b
Entry
1
2
3
4
5
6
7
8
Solvent
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
DMAc
EtOH
DMSO/H O (5/1)
DMSO/H O (2/1)
DMSO/H O (1/1)
Additive
K3PO4
NaOAc
Yield/%
15
50
2
2
5
2
-aminobenzenethiols. Sheibani
reported the synthesis
20
of 1,4-benzothazines by using acyclic 1,3-bielectorphiles
and binucleophiles such as 1,3-dicarbonyl, enaminones and
2
Cs CO3
Triethylamine 20
KOH
2
5
Trace
2
1
,2’-disulfanediyldianiline. Also,heobtained2,3-disubstituted
,4-benzothiazines at ambient temperature and in aqueous
media from 2-aminobenzenethiol and 1,3-dicarbonyls by
c
NH Cl
50
58
70
4
K2HPO
4
12
KH PO4
oxidative cyclocondensation.
2
Another method for phenothiazine synthesis has
been developed by Jain through the condensation of
o-aminobenzenethiol with 1,3-dicarbonyls in dimethyl
9
KH PO4
Trace
2
c
10
11
12
13
14
15
KH PO4
50
2
KH PO4
10
70
80
86
75
2
2
6
sulfoxide.
Our efforts are continuing into studying the
KH PO4
2
2
cleavage reaction of dicarbonyls without a non-transition
KH PO4
2
2
2
7,28
metal.
We now report a facile synthetic method obtaining
KH PO4
2
2
1,4-benzothiazines from the cleavage reaction of benzothiazole
DMSO/H O (1/2)
KH PO4
2
2
with 1,3-dicarbonyls under mild conditions.
d
16
DMAc/H O (1/1)
KH PO4
65
2
2
a
Results and discussion
Reaction conditions: benzothiazole (0.5 mmol), 1,3-cyclohexanedione (1 mmol), base
1 mmol), solvent (2.0 mL), 80 °C, stirred for 3 days under air.
(
Initially, potassium phosphate was employed in the reaction of
benzothiazole 1a and cyclohexane-1,3-dione 2b in dimethyl
sulfoxide (DMSO) at 80 ºC under air for 3 days (Table 1,
b
Yields obtained after column chromatography.
c
d
Reaction time of 6 days.
Reaction time of 7 days.
H
N
NH2
SH
O
O
DMSO
+
140-165 °C
S
O
Jain's work 26
H
N
N
S
O
O
KH PO
+
2
4
Air, 80°C, DMSO/H O
S
2
O
our work
*
Correspondent. E-mail: yyuan@yzu.edu.cn

658 JOURNAL OF CHEMICAL RESEARCH 2015
a
Table 2 Condensation reaction of benzothiazoles (1) and 1,3-dicarbonyls (2)
H
N
O
O
R1
S
2a
O
H
N
S
O
O
N
R1
KH2PO4, 3 days, 80°C
DMSO:H2O (1:1)
+
R1
S
2
b
c
O
O
1
H
N
O
O
R =H, Cl, NO
1
2
R1
S
2
3
b
Entry
R1
Dicarbonyls
Product
Yield/%
M.p./°C
Lit. m.p./°C
1
2
3
4
5
6
7
8
9
H
H
H
NO2
NO2
NO2
Cl
Cl
Cl
2a
2b
2c
2a
2b
2c
2a
2b
2c
3a
3b
3c
3d
3e
3f
3g
3h
3i
60
86
80
60
72
82
40
70
85
216–218
216–220
238–240
288–290
278–280
296–298
290–292
285–287
205–208
–
2
6
202–208
212–214
2
5
–
–
–
–
–
–
a
b
Reaction conditions: a mixture of 1 (0.5 mmol), 2 (1 mmol), KH PO (1 mmol), DMSO (2 mL) and water (2 mL) were placed in a 15 mL flask, stirred for 3 days at 80 ºC.
Yields obtained after column chromatography.
2
4
the reaction and the high pKa value of the additives could not
promote the formation of the product.
yield due to the high reactivity of this 1,3-dicarbonyl. When
benzothiazole 1a reacted with 2c in the presence of KH PO ,
2
4
Encouraged by these results, we investigated the influences of
different additives on the reaction (Table 1, entries 6–8). Among
these additives, potassium dihydrogen phosphate (KH PO )
the corresponding product 3c could be generated in 80% yield.
Meanwhile, cyclopentane-1,3-dione 2a showed fewer reactivity
in comparison with 2b and 2c, while it was treated with
different benzothiazoles under the same conditions. The nitro
group and the chloro group in the phenyl ring of benzothiazole
decreased the yields of the reaction. The structure of the product
3g has been shown in Fig. 1, and the details of the crystal were
shown in Table 3. However, the reaction of benzothiazole with
noncyclic1,3-dicarbonyls could not be carried out easily.
2
4
is generally the best additive in this reaction. The acceptable
yield of product could be achieved using KH PO in DMSO
2
4
(
Table 1, entry 8). Next, several solvents were also screened for
the reaction, such as DMF, N, N-dimethylacetamide (DMAc),
and ethanol (Table 1, entries 9–11), but they could not give
satisfactory results in comparison with DMSO. The best yield
of the corresponding product 3b (86%) was achieved when
DMSO was mixed with water in the ratio 1:1 (Table 1, entry 14).
Using the best conditions, different cyclic 1,3-dicarbonyls 2
were reacted with the substituted benzothiazoles 1 to test the
reaction scope (Table 2). Fortunately, most substrates could
react well under the optimal conditions. 5,5-Dimethylcyclo-1,3-
dione 2c reacted with the substituted benzothiazoles in better
Table 3 Crystallographic data and structure refinement details for 3g
Empirical formula
C H ClNOSNa
11 8
Formula mass
Crystal system
Space group
236.69
Orthorhombic
P c a 21
17.659(4)
4.6932(10)
12.051(2)
90
a/Å
b/Å
c/Å
α/°
β/°
γ/°
90
90
998.8(4)
4
1.574
484.0
3
V/Å
Z
-
3
dcalcd/g cm
F(000)
Reflections collected
R(int)
2097/1491
0.0655
0.1025, 0.0580
1
2
R , wR [I > 2σ(I)]
1
2
R , wR (all data)
0.1096, 0.0977
1426308
CCDC reference number
Fig. 1 X-ray crystal structure of product 3g.

JOURNAL OF CHEMICAL RESEARCH 2015 659
3
270, 2961, 2873, 1590, 1481, 1386, 1328, 1254, 1145, 881, 827;
Experimental
1
H NMR (600 MHz, DMSO-d , ppm): 9.39 (s, 1H), 7.75 (d, J = 8.4Hz,
6
All commercial reagents and solvents were used as received
without further purification unless specified, and reaction solvents
were distilled. Melting points were determined in capillaries and
1H), 7.55 (s, 1H), 6.63 (d, J = 8.8 Hz, 1H), 2.21 (s, 2H), 2.19 (s, 2H),
13
1.00 (s, 6H); C NMR (150 MHz, DMSO-d , ppm): 189.5, 152.6,
6
143.6, 143.3, 124.0, 121.9, 121.3, 115.1, 98.5, 49.6, 40.9, 31.6, 27.5;
1
13
the thermometer is uncorrected. H NMR and C NMR spectra
were obtained with Bruker AVANCE 600 spectrometer in
+
+
MS (EI): m/z = 290 [M] . HRMS-(ESI) (m/z) (M+Na) calcd for
C H N O SNa 313.0617; found: 313.0610.
a
14
14
2
3
DMSO-d . IR spectra were recorded with a Bruker Tensor 27 FT-IR
6
7
-Chloro-2,9-dihydro-1H-cyclopenta[b][1,4]benzothiazin-3-
spectrophotometer using KBr pellets. GC-MS was performed on a
Finnigan Trace DSQ chromatograph. High-resolution mass spectra
were obtained on UHR-TOF MAXis.
one (3g): Yield 40%; orange solid; m.p. 290–292 ºC; IR (KBr)
-1
cm : 3447, 3225, 2920, 1658, 1593, 1523, 1467, 1305, 896, 859, 799;
1
H NMR (600 MHz, DMSO-d , ppm): 9.59 (s, 1H), 6.77–6.84, (m,
6
Synthesis of 3; general procedure
2H), 6.56 (s, 1H), 2.47 (t, J = 4.2 Hz, 2H), 2.27 (t, J = 4.2 Hz, 2H);
13
C NMR (150 MHz, DMSO-d , ppm): 195.3, 166.2, 138.4, 131.3,
A mixture of benzothiazole 1a (67.5 mg, 0.5 mmol), cyclohexane-
6
+
1
28.4, 124.0, 116.6, 115.8, 100.4, 32.6, 25.6; MS (EI): m/z = 237 [M] .
HRMS-(ESI) (m/z) (M+Na) calcd for C H ClNOSNa 259.9907;
1,3-dione 2b (112 mg, 1 mmol), KH PO (136 mg, 1 mmol), DMSO
2 4
+
(
2 mL) and water (2 mL) were placed into a 15 mL flask under air.
11
8
found: 259.9916.
-Chloro-2,3-dihydro-1H-phenothiazin-4(10H)-one (3h): Yield
The reaction mixture was stirred in oil bath for 3 days at 80 ºC. The
progress of the reaction was monitored by TLC.
When the reaction was complete, it was neutralised with a saturated
KHCO3 aqueous solution, and extracted with ethyl acetate (3 ×
8
-1
70%; orange solid; m.p. 285–287 ºC; IR (KBr) cm : 3444, 3253,
2
943, 1714, 1636, 1574, 1502, 1462, 1330, 1291, 927, 878, 804;
1
H NMR (600 MHz, DMSO-d , ppm): 8.99 (s, 1H), 6.51–6.97 (m,
10 mL). The extract was washed with water (3 × 5 mL) and dried
6
2
H), 6.56 (s, 1H), 2.32 (t, J = 6.0 Hz, 2H), 2.26 (t, J = 6.0 Hz, 2H),
over anhydrous Na SO . After drying, it was concentrated under
2
4
13
1.80–1.88 (m, 2H); C NMR (150 MHz, DMSO-d , ppm): 189.3,
reduced pressure to give the crude product, which was further purified
by silica-gel column chromatography to afford 2,3-dihydro-10H-
phenothiazin-4 (1H)-ones 3b (93.2 mg, yield: 86%).
6
1
55.5, 138.3, 130.7, 127.6, 123.8, 119.1, 115.0, 100.3, 36.1, 27.9, 20.0;
+
+
MS (EI): m/z = 251 [M] . HRMS-(ESI) (m/z) (M+Na) calcd for
C H ClNOSNa 274.0064; found: 274.0057.
2
,9-Dihydro-1H-cyclopenta[b][1,4]benzothiazin-3-one (3a): Yield
12 10
-1
8-Chloro-2,2-dimethyl-2,3-dihydro-1H-phenothiazin-4(10H)-
6
1
0%; yellow solid; m.p. 216–218 ºC; IR (KBr) cm : 3348, 2907, 1596,
568, 1530, 1472, 1432, 1288, 1286, 750; H NMR (600 MHz, DMSO-d ,
-
1
one (3i): Yield 85%; orange solid; m.p. 205–208 ºC; IR (KBr) cm
6
1
:
3447, 3276, 2958, 2928, 2867, 1728, 1570, 1508, 1467, 1384,
1273, 934, 861, 805; H NMR (600 MHz, DMSO-d , ppm): 8.94
ppm): 9.47 (s, 1H), 6.90 (t, J = 7.3Hz, 1H), 6.73–6.77 (m, 2H), 6.54 (d,
1
13
J = 7.9Hz, 1H), 2.47 (t, J = 4.5Hz, 2H), 2.27(t, J = 4.2Hz, 2H); C NMR
150 MHz, DMSO-d , ppm): 195.2, 166.6, 136.6, 127.5, 127.2, 124.7, 117.3,
6
(
s, 1H), 6.71–6.80 (m, 2H), 6.54 (s, 1H), 2.18 (s, 2H), 2.15 (s, 2H),
(
1
(
6
13
+
0.98 (s, 6H); C NMR (150 MHz, DMSO-d , ppm): 188.9, 153.5,
16.6 , 99.9, 32.5 , 25.6 ; MS (EI): m/z = 203 [M] . HRMS-(ESI) (m/z)
6
+
138.4, 130.7, 127.7, 123.8, 119.1, 115.0, 97.2, 49.7, 41.2, 31.5, 27.5;
M+Na) calcd for C H NOSNa 226.0297; found: 226.0291.
11 9
+
+
2
6
MS (EI): m/z = 279 [M] . HRMS-(ESI) (m/z) (M+Na) calcd for
2
,3-Dihydro-1H-phenothiazin-4(10H)-one (3b):
Yield 86%;
2
6
-1
C H ClNOSNa 302.0377; found: 302.0369.
yellow solid; m.p. 216–220 ºC (lit. 202–208 ºC), IR (KBr) cm : 3347,
016, 2906, 1564, 1515, 1468, 1431, 1353, 1294, 1564, 1515, 1294, 746;
14 14
3
1
Conclusion
H NMR (600 MHz, DMSO-d ，ppm): 8.91 (s, 1H), 6.86 (t, J = 6.4 Hz,
6
1
2
H), 6.79-6.69 (m, 2H), 6.54 (d, J = 7.7 Hz, 1H), 2.32 (t, J = 6.0 Hz,
H), 2.24 (t, J = 6.0 Hz, 2H), 1.87-1.76 (m, 2H); C NMR (150 MHz,
We developed a new approach to synthesise the 2,3-dihydro-
1H-phenothiazin-4(10H)-ones and the cyclopenta[b][1,4]
benzothiazines under a mild and environment benign
conditions. This reaction could be carried out without any
transition metals with good to moderate yield.
13
DMSO-d , ppm): 189.0, 156.0, 136.6, 126.8, 126.4, 124.5, 119.9, 115.6,
9
6
+
7.8, 36.1, 28.0, 20.1; MS (EI): m/z = 217 [M] .
2
5
2
,2-Dimethyl-2,3-dihydro-1H-phenothiazin-4(10H)-one
(3c):
2
5
Yield 80%; orange solid; m.p. 238–240 ºC (lit. 212-214 ºC)，IR (KBr)
cm : 3432, 3066, 3025, 2957, 2870, 1574, 1519, 1472, 1427, 1355,
-1
Electronic Supplementary Information
1
1306, 748; H NMR (600 MHz, DMSO-d ，ppm): 8.86 (s, 1H), 6.86
1
13
6
The ESI including H and C NMR spectra of the compounds is
available through stl.publisher.ingentaconnect.com/content/stl/
jcr/supp-data.
(t, J = 5.9 Hz, 1H), 6.74 (m, 2H), 6.54 (d, J = 7.6 Hz, 1H), 2.28 (s, 2H),
13
2
1
2
.23(s, 2H), 0.99 (s, 6H); C NMR (150 MHz, DMSO-d , ppm): 188.4,
6
53.9, 136.6, 126.8, 126.4, 124.4, 119.8, 115.6, 96.5, 49.6, 41.2, 31.4,
+
7.5; MS (EI): m/z = 245 [M] .
This work was supported by the Priority Academic Program
Development of Jiangsu Higher Education Institutions.
6
-Nitro-2,9-dihydro-1H-cyclopenta[b][1,4]benzothiazin-3-one
-1
(
3
3d): Yield 60%; purple solid; m.p. 288–290 ºC; IR (KBr) cm : 3439,
233, 3052, 1665, 1595, 1534, 1500, 1473, 1338, 1303, 1252, 886, 824;
1
Received 23 July 2015; accepted 5 October 2015
Paper 1503507 doi: 10.3184/174751915X14449331711796
Published online: 1 November 2015
H NMR (600 MHz, DMSO-d , ppm): 10.02 (s, 1H), 7.77 (d, J = 8.4Hz,
6
1H), 7.60 (s, 1H), 6.61 (d, J = 8.8 Hz, 1H), 2.48 (t, J = 4.2 Hz, 2H), 2.32
13
(t, J = 4.8 Hz, 2H); C NMR (150 MHz, DMSO-d , ppm): 195.9, 165.8,
6
1
43.6, 143.4, 124.4, 122.0, 119.7, 115.9, 101.6, 32.8, 25.6; MS (EI):
+
+
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11
8
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3
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7
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6
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