Method for the Synthesis of Phenothiazines via a Domino Iron-Catalyzed C-S/C-N Cross-Coupling Reaction

Article abstract of DOI:10.1021/acs.joc.5b00568

An environmentally benign and efficient method has been developed for the synthesis of phenothiazines via a tandem iron-catalyzed C-S/C-N cross-coupling reaction. Some of the issues typically encountered during the synthesis of phenothiazines in the presence of palladium and copper catalysts, including poor substrate scope, long reaction times and poor regioselectivity, have been addressed using this newly developed iron-catalyzed method.

Full text of DOI:10.1021/acs.joc.5b00568

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Article
Method for the Synthesis of Phenothiazines via a Domino
Iron-Catalyzed C–S/C–N Cross-Coupling Reaction
Weiye Hu, and Songlin Zhang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00568 • Publication Date (Web): 01 Jun 2015
Downloaded from http://pubs.acs.org on June 7, 2015
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Method for the Synthesis of Phenothiazines via a Domino
Iron-Catalyzed C–S/C–N Cross-Coupling Reaction
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Weiye Hu and Songlin Zhang*
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical
Engineering and Materials Science, Dushu Lake Campus, Soochow University, Suzhou, 215123,
People’s Republic of China.
Fax: +86ꢀ512ꢀ65880352. Eꢀmail: zhangsl@suda.edu.cn
X
X
FeSO4 7H2O
phen
KOtBu, DMF
1350C, 24 h
S
SH
O
R2
R2
R1
R1
+
N
H
N
H
X= I, Br, Cl
R1=H, Cl
19%- 96%
R2= H, Me, -CF3, Cl, heterocycle
Abstract:
An environmentally benign and efficient method has been developed for the
synthesis of phenothiazines via a tandem ironꢀcatalyzed CꢀS/CꢀN crossꢀcoupling
reaction. Some of the issues typically encountered during the synthesis of
phenothiazines in the presence of palladium and copper catalysts, including poor
substrate scope, long reaction times and poor regioselectivity, have been addressed
using this newly developed ironꢀcatalyzed method.
Introduction
In recent year, the transitionꢀmetal have been the main force in the crossꢀcoupling
reactions which play an important role in the formation of CꢀN bond and CꢀS bond of
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some important compounds in biological, pharmaceutical and materials sciences1,
especially the iron ,which have a closely relation with the life of the human being.
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Since the pioneering work of Tamura and Kochi2, iron salts as catalyst have
caused widespread concern and made great progress. In the last few years, there has
been a significant increase in the number of reports pertaining to the development of
ironꢀcatalyzed reactions in organic synthesis, where iron has shown several significant
advantages over other metals, such as being more abundant, commercially
inexpensive and environmentally friendly3. Compared with palladium, the use of iron
is particularly suitable for reactions involving the preparation of therapeutic agents for
human consumption. The ironꢀcatalyzed formation of CꢀN bond and CꢀS bond have
been reported several times4ꢀ5. However, it is rare that one ironꢀcatalyzed system can
be effective for both CꢀN coupling and CꢀS coupling, because every catalyzed system
has its own specificity for specific compounds.
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Phenothiazines represent an important class of heterocyclic compounds which
play an important role in the treatment of mental illnesses6 and also been used as
anodyne, peroxidation inhibitors and optoelectronic materials7. In recent year, some
new methods for the synthesis of phenothiazines have been reported8ꢀ11. Compared
with the traditional methods12, those methods indeed solved some defects like toxicity
by product(like H2S) and low regioselectivity. For example, Jørgensen’s group
reported an elegant method for the synthesis of substituted phenothiazines via the
palladiumꢀcatalyzed three component coupling reaction of substituted
1ꢀbromoꢀ2ꢀiodobenzenes with primary amines and 2ꢀbromobenzenethiol in 200810.
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And in 2010, Ma et al11a reported a CuI/Lꢀprolineꢀcatalyzed CꢀS/CꢀN bond formation
of 2ꢀiodoanilines and 2ꢀbromobenzenethiolsby controlling the reaction temperature
and time (i.e., 90 °C for 24–48 h followed by 110 °C for 48–96 h). Although many
catalyzedsystems have been reported for the synthesis of phenothiazines, there are no
ironꢀcatalyzed versions have been researched. With this in mind, it was envisaged that
an ironꢀcatalyzed reaction could be developed for the synthesis of substituted
phenothiazines. Herein, we report the results of our preliminary investigations
towards the development of this protocol.
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Results and Discussion
Given that there has no reports in the literature to date pertaining to the use of iron
as a catalyst for the coupling reaction of an arylamine and aryl halide, we used an
acylꢀprotected arylamine14 to investigate this reaction because it could be readily
removed upon completion of the coupling reaction.13 The reaction of 1a with
1,2ꢀdibromobenzene was used as themodeltransformation to identify the optimum
reaction conditions by screening a variety of different iron salts, bases, ligands and
solvents (Table 1). Several iron salts were screened in this reaction, including Fe2O3,
FeSO4·7H2O, Fe2(SO4)3, Fe(acac)3, FeCl3, FeCl2·4H2O and Fe(NO2)3·9H2O, and
FeSO4·7H2O was found to give the best results with the desired product 3a being
formed in a yield of 52% (Table 1, Entries 1ꢀ7). Several other bases, including
NaOCH3, K2CO3, Cs2CO3 and NaOAc, were also evaluated under the same conditions
using FeSO4·7H2O, but all of these bases failed to provide better results than KOtBu
(Table 1, Entries 8ꢀ11).
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Several ligands were also screened in the model reaction, and the results revealed
that the nature of the ligand has a dramatic impact on the yield of the reaction. For
example, the use of 1,10ꢀphenanthroline gave 10Hꢀphenothiazine in 70% yield,
whereas DABCO, bisꢀpyridyl and Lꢀproline provided much lower yields of 11%, 19%
and 14%, respectively (Table 1, entries 12ꢀ15). The reaction was also conducted in a
variety of different solvents to determine the impact of the solvent on the outcome of
the reaction. DMF was found to be the best solvent for the transformation, because it
provided a much higher of the desired product than toluene, DMSO or
acetonitrile(Table 1, entries 16ꢀ18). Some clean solvents, including ethanol and THF,
were appliedin the reaction, but no product was obtained (Table 1, entries 19ꢀ20).
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Control experiments weretaken in the absence ofFeSO4·7H2O or
KOtBurespectively, no product was obtained (Table, entries 21ꢀ22).In view of the fact
thatthe trace metals in catalytic, as is wellꢀknown, sometime could play an important
role in the reaction15, highꢀpurityFeSO4·7H2O(99.999%) was applied in the reaction
(Table 1, entry 24).The product was formed in a yield of 73% which was similar with
the one of FeSO4·7H2O (99%).At last, the dosage of FeSO4·7H2O was reduce to 10
mmol%, but only 60% yield was obtained (Table 1, entry 25). Taken together, the
results of these screening experiments revealed that the optimal conditions for the
reaction were FeSO4·7H2O (20 mol%), 1,10ꢀphenanthroline (20 mol%) and KOtBu in
DMF at 135 °C.
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Table 1: Optimization of the reaction of1a with 1,2ꢀdibromobenzenea
S
7
8
9
SH
Br
Iron salt
Base
O
+
N
Ligand
N
H
Br
H
3a
1a
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S
S
N
NH
Br
5a
4a
O
O
Entry
1
2
3
4
Iron salt
Fe2O3
FeSO4·7H2O
Fe2(SO4)3
Fe(acac)3
FeCl3
Lc
Base
Solv.
Y(%)b
42
52
44
46
47
44
35
40
32
37
29
11
70
19
14
trace
17
trace
0
A
A
A
A
A
A
A
A
A
A
A
B
C
D
E
C
C
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
NaOMe
K2CO3
Cs2CO3
NaOAc
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
none
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
PhMe
DMSO
MeCN
EtOH
THF
5
6d
7
FeCl2·4H2O
Fe(NO2)3·9H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
FeSO4·7H2O
none
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9
10
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12
13
14
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16
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18
19
20
21
22
23
24e
25f
C
C
C
C
0
0
0
trace
73
60
DMF
DMF
DMSO
DMF
DMF
C
KOtBu
KOH
none
FeSO4·7H2O
FeSO4·7H2O
none
C
KOtBu
KOtBu
C
a Reaction conditions: 1a (0.3 mmol), 1,2ꢀdibromobenzene (1.5 equiv), iron salt
(20 mmol%), base (4equiv), ligand (20mmol%) were added to a solvent (2 mL)
and react at 135 0C for 24 h under N2. bA yield based on 1a after silica gel
chromatography. c A=TMEDA, B= DABCO, C= 1,10ꢀphenanthroline, D=
dipyridyl, E= Lꢀproline. d FeCl2·4H2O in a purity of 99.99%.eFeSO4·7H2O in a
purity of 99.999% from alfa.fwith iron salt in a dosage of 10 mmol%.
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It is noteworthy that the intermediate product 4a was formed as a byꢀproduct
under the optimized conditions via the CꢀS cross coupling reaction of
Nꢀ(2ꢀmercaptophenyl)acetamide (1a) with 1,2ꢀdibromobenzene. Furthermore, the
subsequent intramolecular CꢀN cross coupling of 4a gave the Nꢀacetylated
phenothiazine 5a. These results demonstrated that the oneꢀpot reaction includes three
different processes, which are shown in Table 1.
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With the optimized reaction conditions in hand, we proceeded to investigate the
substrate scope of the reaction using avariety of different aryl 1,2ꢀdihalobenzenes
(Table 2). Nꢀ(2ꢀMercaptophenyl)acetamide was reacted with a variety of different
1,2,ꢀdihalobenzene
substrates,
including
1ꢀbromoꢀ2ꢀchlorobenzene,
1ꢀbromoꢀ2ꢀiodobenzene and
1ꢀchloroꢀ2ꢀiodobenzene,
1,2ꢀdibromobenzene,
1,2ꢀdichlorobenzene under the optimized conditions, with the desired
10Hꢀphenothiazine being formed in moderate to excellent yields (Table 2, entries
1–5). Even the least reactive of these substrates, 1,2ꢀdichlorobenzene, provided the
desired product under the optimized conditions, albeit in a low yield of 20% (Table 2,
entry 5). The optimized conditions were also applied to a series of substituted
1,2ꢀdihalobenzenes,
including
2ꢀbromoꢀ1ꢀiodoꢀ4ꢀmethylbenzene
and
2ꢀbromoꢀ4ꢀ(trifluoromethyl)ꢀ1ꢀiodobenzene, with the corresponding substituted
phenothiazines being formed in only 19% and 40% yields, respectively (Table 2,
entries 6–7). With a mass of by products were observed, we think the methyl
andtrifluoromethylaffect the reaction in the process of CꢀN cross coupling by lower
the activity of halogen in metaꢀposition. It is noteworthy that the reactions of
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2ꢀbromoꢀ4ꢀchloroꢀ1ꢀiodobenzene and 4ꢀchloroꢀ1,2ꢀdiiodobenzene resulted in a
mixture of two regioisomers in both cases in a high total yield (Table 2, entries 8–9).
The result may be caused by the diminution of the gap of theactivity between two
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reaction centers.
Table 2: Reagent scope of the reactiona
X
S
SH
Fe
O
R2
R2
R1
R1
+
Ligand/base
X
N
H
N
H
Entry
1
Substrate 1
Substrate 2
Product
Y(%)
72
I
S
SH
O
Br
Br
N
H
N
H
3a
S
SH
O
2
3
4
5
6
7
70
81
80
20
19
40
50
21
N
H
N
H
Br
Br
3a
S
SH
O
Cl
N
H
N
H
3a
S
SH
O
I
N
H
N
H
Cl
3a
3a
3b
S
SH
O
Cl
N
H
N
H
Cl
I
S
SH
O
Br
I
N
N
H
H
S
SH
O
F3C
Br
N
CF3
N
H
H
3c
S
SH
O
Cl 3d
I
N
H
8
N
H
Cl
Br
S
Cl
N
H
3e
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S
4
5
6
7
70
SH
I
I
Cl 3d
N
H
O
9
N
H
Cl
S
Cl
8
9
14
80
N
H
3e
10
11
12
13
14
15
16
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18
19
20
21
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S
SH
I
O
10
11
12
13
14
N
H
Cl 3d
Cl 3d
Cl 3d
Cl 3d
Cl 3d
Cl
Cl
Cl
Cl
Cl
N
H
Br
S
SH
Br
O
92
69
85
35
63
32
65
20
63
70
60
N
H
N
H
Br
Br
S
SH
O
N
H
N
H
Cl
I
S
SH
O
N
H
N
H
Cl
Cl
S
SH
O
N
H
N
H
Cl
S
SH
Cl 3f
Cl
Cl
N
H
O
I
Cl
N
H
15
16
Cl
S
Cl
Br
N
H
3g
S
Cl 3f
Cl
N
H
SH
I
I
O
Cl
S
Cl
N
Cl
H
Cl
N
H
3g
Br
S
N
SH
O
17
18
19
N
N
Br
N
H
N
H
3h
Br
Br
S
N
SH
O
Cl
N
Cl
N
H
H
3i
Br
Br
S
N
SH
O
N
N
N
H
H
3j
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Br
Br
S
N
SH
O
20
78
N
Cl
N
Cl
N
H
H
3k
N
Br
S
N
N
SH
O
21
22
90
96
N
Br
N
H
N
H
3l
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
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30
31
32
33
34
35
36
37
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45
46
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49
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52
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N
N
Br
Br
S
N
SH
O
Cl
N
N
Cl
N
H
H
3m
a Reaction condition : Substrate 1 ( 0.3 mmol ), Substrate 2 ( 0.45 mmol ),
FeSO4·7H2O ( 0.06 mmol ), phen ( 0.06 mmol), KOtBu( 1.2 mmol ), DMF
( 2 mL ), at 135 0C for 24 h.
Several exciting results were obtained when the substrate scope was expanded to
evaluate the use of Nꢀ(5ꢀchloroꢀ2ꢀmercaptophenyl)acetamide under the optimized
conditions.
Most
of
the
1,2ꢀdihalobenzene
substrates,
including
1ꢀbromoꢀ2ꢀchlorobenzene,
1ꢀchloroꢀ2ꢀiodobenzene,
1,2ꢀdibromobenzene,
1ꢀbromoꢀ2ꢀiodobenzene and 1,2ꢀdichlorobenzene reacted smoothly with
Nꢀ(5ꢀchloroꢀ2ꢀmercaptophenyl)acetamide to give 2ꢀchloroꢀ10Hꢀphenothiazine in
yields of up to 92% (Table 2, entries 10ꢀ14). High total yields were also obtained
when
Nꢀ(5ꢀchloroꢀ2ꢀmercaptophenyl)acetamide
was
reacted
with
2ꢀbromoꢀ4ꢀchloroꢀ1ꢀiodobenzene and 4ꢀchloroꢀ1,2ꢀdiiodobenzene (Table 2, entries 15
and 16).
The use of heterocyclic compounds as substrates for this reaction was also
investigated using 2,3ꢀdibromopyridine, 2,3ꢀdibromoꢀ5ꢀmethylpyridine and
2,3ꢀdibromoquinoxaline. Pleasingly, the corresponding heterocyclic phenothiazines
were
obtained
in
good
yields
when
2,3ꢀdibromopyridine
and
2,3ꢀdibromoꢀ5ꢀmethylpyridine were used as substrates (Table 2, entries 17ꢀ20).
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Furthermore,
2,3ꢀdibromoquinoxaline
reaction
smoothly
with
both
5
6
7
8
9
Nꢀ(2ꢀmercaptophenyl)acetamide and Nꢀ(5ꢀchloroꢀ2ꢀmercaptophenyl)acetamide to
afford the corresponding coupling products in 90 and 96% yields, respectively (Table
2, entries 21–22). This work therefore represents the first reported example of the
synthesis of phenothiazines from a quinoxaline.
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Conclusion
In summary, anefficient method has been developed for the synthesis of
phenothiazines using an iron salt as a catalyst. This method has been successful
applied to the CꢀN coupling of aryl amines and aryl halides for the synthesis of
serviceable compounds. Work is in progress to understand the mechanism.
Experimental Section
General details
All of the reagents and solvents were used directly as obtained commercially unless otherwise noted.
Petroleum ether (PE) used refers to the 60ꢀ90 0C boiling point fraction of petroleum. Column
1
chromatography was performed with 300ꢀ400 mesh silica gel using flash column techniques. H and 13C
NMR spectra were determined in CDCl3 or DMSOꢀd6 on a 400MHz spectrometer and chemical shifts were
measured relative to the signals for residual chloroform (7.26 ppm), or DMSO (2.50 ppm) in the deuterated
solvent, unless otherwise stated. Chemical shifts in 13C NMR spectra are reported relative to the central line
of the DMSO (δ = 40.00 ppm).
Synthesis of 10H-phenothiazine:
Nꢀ(2ꢀmercaptophenyl)acetamide(50.1mg, 0.3 mmol), FeSO4·7H2O(16.68mg, 0.06
mmol), 1,10ꢀphenanthroline(10.08mg, 0.06 mmol) and KOtBu(134.4mg, 1.2 mmol)
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were weighed into an ovenꢀdried Schlenk tube which was sealed with a plug and an
nitrogen atmosphere was established. Then, 1,2ꢀdibromobenzene(53.8ꢁL,0.45 mmol)
and DMF(2 mL) was added via syringe. The Schlenk tube was heated to 135 ºC and
stirring for 24 h. When the reaction complete, the homogeneous mixture was cooled
to room temperature and diluted with water and ether. The organic solution was
washed with brine, dried (Na2SO4), and purified by column chromatography(ethyl
acetate: petroleum ether=1:80) to give desired 10Hꢀphenothiazine.
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10H-phenothiazine(3a)11a: obtained as a celadon solid;mp 184ꢀ185 C. HNMR
(400 MHz, DMSOꢀd6), (ppm): 8.58 (s, 1H), 7.00ꢀ6.96 (m, 2H), 6.91ꢀ6.89 (d, J=7.6,
2H), 6.76ꢀ6.68 (m, 4H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 142.6, 128.0,
126.7, 122.2, 116.8, 114.9.LCꢀMS: [M + H]+ m/z = 200.0.
2-methyl-10H-phenothiazine(3b)11a: obtained as a obtained as a rufous solid;
0
1
isolated yield: 12.14 mg (19%); mp 186ꢀ187.5 C. HNMR (400 MHz, DMSOꢀd6),
(ppm): 8.50 (s, 1H), 6.99ꢀ6.95 (m, 1H), 6.90ꢀ6.88 (m, 1H), 6.79ꢀ6.67 (m, 3H),
6.59ꢀ6.51 (m, 2H), 2.15 (s, 3H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 142.6,
142.5, 137.4, 127.9, 126.7, 126.5, 123.0, 122.1, 117.1, 115.6, 114.9, 113.4, 21.1.
LCꢀMS: [M + H]+ m/z = 214.1.
2-(trifluoromethyl)-10H-phenothiazine(3c)11a: obtained as a yellow solid;
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isolated yield: 32.04 mg(40%); mp188ꢀ190 °C. HNMR (400 MHz, DMSOꢀd6),
(ppm): 8.88 (s, 1H), 7.12ꢀ7.00 (m, 3H), 6.94ꢀ6.89 (m, 2H), 6.79 (t, J=7.52, 1H), 6.65
(d, J=8, 1H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 143.1, 141.4, 128.6
1
(2JCF=31Hz), 128.0, 126.7, 125.8 (q, JCF=270.34 Hz), 123.1, 123.0, 122.5, 118.5,
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115.7, 115.21, 110.2. LCꢀMS: [M + H]+ m/z = 268.0.
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2-chloro-10H-phenothiazine(3d)11a: obtained as a rufous solid; mp196ꢀ198 °C.
1HNMR (400 MHz, DMSOꢀd6), (ppm): 8.78 (s, 1H), 7.02ꢀ6.98 (m, 1H), 6.92ꢀ6.90 (d,
J=8.08, 2H), 6.80ꢀ6.76 (m, 2H), 6.70ꢀ6.66 (m, 2H). 13C {1H}ꢀNMR (100 MHz,
DMSOꢀd6, δ ppm): 144.0, 141.6, 132.3, 128.3, 127.9, 126.8, 122.8, 121.7, 116.5,
116.0, 115.1, 114.2. LCꢀMS: [M + H]+ m/z = 234.1.
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3-chloro-10H-phenothiazine(3e)10: obtained as a rufous solid; mp 200ꢀ201 °C .
1HNMR (400 MHz, DMSOꢀd6), (ppm): 8.73 (s, 1H), 7.03ꢀ6.98 (m, 3H), 6.93ꢀ6.91 (m,
1H), 6.79ꢀ6.75 (m, 1H), 6.68ꢀ6.65 (m, 2H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ
ppm): 142.1, 141.6, 128.3, 127.7, 126.8, 125.9, 125.4, 122.6, 119.1, 116.0, 115.9,
115.1. LCꢀMS: [M + H]+ m/z = 234.1.
2,8-dichloro-10H-phenothiazine(3f)15: obtained as
a
yellow solid; mp
1
267ꢀ268.5°C. HNMR (400 MHz, DMSOꢀd6), (ppm): 8.94 (s, 1H), 6.94ꢀ6.92 (d,
J=8.2, 2H), 682ꢀ6.80 (m, 2H), 6.67 (s, 2H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ
ppm):143.0, 132.5, 128.1, 122.3, 115.7, 114.5. LCꢀMS: [M + H]+ m/z = 268.9.
2,7-dichloro-10H-phenothiazine(3g)16: obtained as
a
yellow solid; mp
214ꢀ215.5 °C. 1HNMR (400 MHz, DMSOꢀd6), (ppm): 8.90 (s, 1H), 7.05ꢀ7.03 (m, 2H),
6.94ꢀ6.92 (d, J=8.24, 1H), 6.81ꢀ6.78 (m, 1H), 6.68ꢀ6.63 (m, 2H). 13C {1H}ꢀNMR
(100 MHz, DMSOꢀd6, δ ppm): 143.5, 140.6, 132.6, 128.1, 128.0, 126.1, 126.0, 122.0,
118.8, 116.2, 115.2, 114.4. LCꢀMS: [M + H]+ m/z = 268.9.
5H-Pyrido[2,3-b][1,4]benzothiazine(3h)17: obtained as a yellow solid; isolated
yield: 37.8 mg(63%); mp 112ꢀ113 °C. 1HNMR (400 MHz, DMSOꢀd6), (ppm): 9.19 (s,
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H), 7.80 (d, J=3.8, 1H), 7.26 (d, J=7.16, 1H), 7.01ꢀ6.90 (m, 2H), 6.83ꢀ6.70 (m, 3H).
13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 153.7, 146.1, 141.3, 134.3, 128.2,
126.4, 123.0, 118.4, 115.8, 115.7, 112.7. LCꢀMS: [M + H]+ m/z = 201.1.
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7-chloro-5H-Pyrido[2,3-b][1,4]benzothiazine(3i)(new): obtained as a yellow
1
solid; isolated yield: 49.14 mg(70%); mp 217ꢀ218.5 °C. HNMR (400 MHz,
DMSOꢀd6), (ppm): 9.34 (s, 1H), 7.83ꢀ7.81 (m, 1H), 7.29 (d, J=7.48, 1H), 6.93 (d,
J=8.2, 1H), 6.85ꢀ6.74 (m, 3H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 152.9,
146.3, 142.8, 134.5, 132.5, 127.7, 122.4, 118.9, 115.0, 114.9, 112.4. LCꢀMS: [M +
H]+ m/z = 235.0. HRMS (ESI/TOFꢀQ) m/z: [M + H]+Calcd for C11H7ClN2SH
235.0091; Found 235.0100.
3-methyl-5H-Pyrido[2,3-b][1,4]benzothiazine(3j)(new): obtained as a light
yellow solid; isolated yield: 38.52 mg(60%); mp 163.5ꢀ164,5 °C. 1HNMR (400 MHz,
DMSOꢀd6), (ppm): 9.04 (s, 1H), 7.63 (s, 1H), 7.12 (s, 1H), 6.97 (t, J=7.32, 1H), 6.90
(d, J=7.64, 1H), 6.81ꢀ6.73 (m, 2H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm):
151.5, 145.6, 141.7, 134.9, 128.2, 127.3, 126.4, 122.7, 115.7, 115.5, 112.3, 17.3.
LCꢀMS: [M + H]+ m/z = 215.1.HRMS (ESI/TOFꢀQ) m/z: [M + H]+Calcd for
C12H10N2SH 215.0637; Found 215.0629
3-methyl-7-chloro-5H-Pyrido[2,3-b][1,4]benzothiazine(3k)(new): obtained as a
1
light yellow solid; isolated yield:58.03 mg (78%); mp 219ꢀ220 °C. HNMR (400
MHz, DMSOꢀd6), (ppm): 9.20 (s, 1H), 7.65 (s, 1H), 7.15 (s, 1H), 6.92 (d, J=8.2,
1H), 6.82ꢀ6.77 (m, 2H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 150.7, 145.8,
143.2, 135.1, 132.5, 127.9, 127.7, 122.1, 114.9, 114.8, 112.1, 17.3. LCꢀMS: [M + H]+
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m/z = 248.9.HRMS (ESI/TOFꢀQ) m/z: [M + H]+Calcd for C12H9ClN2SH 249.0248;
Found 249.0244.
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12H-Quinoxalino[2,3-b][1,4]benzothiazine(3l)18: obtained as a yellow solid;
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isolated yield: 67.77 mg(90%); mp 281ꢀ282.5 °C. HNMR (400 MHz, DMSOꢀd6),
(ppm): 10.22 (s, 1H), 7.52ꢀ7.29 (m, 4H), 7.05ꢀ6.99 (m, 2H), 6.87ꢀ6.79 (m, 2H). 13C
{1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 146.0, 145.6, 140.8, 139.6, 136.9, 129.7,
128.4, 127.2, 126.3, 126,2, 126.0, 123.0, 116.4, 115.6. LCꢀMS: [M + H]+ m/z = 252.0.
2-chloro-12H-Quinoxalino[2,3-b][1,4]benzothiazine(3m)18: obtained as a yellow
solid; isolated yield: 82.08 mg (96%); mp 289ꢀ290 °C. 1HNMR (400 MHz,
DMSOꢀd6), (ppm): 10.32 (s, 1H), 7.52ꢀ7.31 (m, 4H), 7.02 (d, J=8.12, 1H), 6.84 (t,
J=7.32, 2H). 13C {1H}ꢀNMR (100 MHz, DMSOꢀd6, δ ppm): 145.4, 145.0, 140.6,
139.7, 138.4, 132.5, 129.8, 127.7, 127,3, 126.6, 126.2, 122.4, 115.6, 114.83. LCꢀMS:
[M + H]+ m/z = 286.0.
ꢀ
ACKNOWLEDGMENT.
We gratefully acknowledge A Project Funded by the Priority Academic Program
Development of Jiangsu Higher Education Institutions, The Project of Scientific and
Technologic Infrastructure of Suzhou (No. SZS201207) and the National Natural
Science Foundation of China (No. 21072143) for financial support.
Supporting Information Available. 1H and 13C NMR spectra for all compounds.
This material is free of charge via the Internet at http://pubs.acs.org
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