Transition-metal-free synthesis of imidazobenzothiazines via domino C-S/C-N bond formation

Article abstract of DOI:10.1007/s00706-014-1264-z

The carbon-heteroatom bond formation is an important research field. Transition-metal-free synthesis of medicinally important heterocycles avoids products of transition metal contamination, and thus it is an environmentally friendly and cost-saving proces

Full text of DOI:10.1007/s00706-014-1264-z

Monatsh Chem (2014) 145:1925–1931
DOI 10.1007/s00706-014-1264-z
ORIGINAL PAPER
Transition-metal-free synthesis of imidazobenzothiazines
via domino C-S/C-N bond formation
•
Xingzhao Tu Lihong Zhou Zhijie Li
•
•
•
Ning Lei Qingle Zeng
Received: 30 December 2013 / Accepted: 15 June 2014 / Published online: 10 September 2014
Ó Springer-Verlag Wien 2014
Abstract The carbon-heteroatom bond formation is an
important research field. Transition-metal-free synthesis of
medicinally important heterocycles avoids products of
transition metal contamination, and thus it is an environ-
mentally friendly and cost-saving process. A transition-
metal-free domino C-S/C-N formation for the synthesis of
imidazobenzothiazines from 2-mercaptobenzimidazoles
and 2-halobenzyl bromides is developed. The desired
products were obtained in good to excellent yields. The
mechanism of domino nucleophilic substitution (SN2) and
nucleophilic aromatic substitution (SNAr) is proposed.
firstly reported the C-N cross-coupling reaction [1–3]. Most
commonly palladium complexes and copper compounds are
used as catalysts to promote the C-N and C-S coupling reac-
tion. But disadvantages, for example, residual transition metal
contaminant, seriously limit their applications. Therefore, to
develop economical, transition-metal-free, and environmen-
tally friendly cascade processes is drawing many chemists’
attention. Early in 2001, Beller first reported a transition-metal-
free intra- and intermolecular C-N coupling with aryl chlorides
with primary and secondary amines as substrates [4]. There-
after, a great number of C-X coupling reactions have been
developed into transition-metal-free reactions [5–15].
Keywords Green chemistry Á Domino reaction Á
Imidazobenzothiazines Á Coupling reaction Á
Transition-metal-free
Heterocycles bearing C-S and C-N bond, for example,
imidazobenzothiazines, have been found with a broad
range of uses in drugs, such as anti-inflammatory [16, 17],
antimicrobial [18, 19], antitubercular [20–23], antifungal
[24, 25], antagonist [26–30], and in functional material
additives [31–33]. In the synthesis of these compounds,
tandem C-S/C-N formation shows obvious advances over
other methods due to their facile one-pot procedure [34–
37]. In addition, recent advances in tandem reactions with
C-X (X=N, S, O) coupling reactions show their great
importance in both methodology development [37–42]
and natural product synthesis [43]. However, these tan-
dem reactions are always carried out in presence of
transition metals. Therefore, development of transition-
metal-free domino C-X (X=N, S, O) bond formation is of
importance.
Introduction
The carbon-heteroatom bond formation is one of the most
important fields in organic chemistry. Numerousmethodshave
been developed in last decades since Ullmann and Goldberg
Electronic supplementary material The online version of this
article (doi:10.1007/s00706-014-1264-z) contains supplementary
material, which is available to authorized users.
As part of our ongoing studies on C-S/C-N cascade coupling
reaction (Scheme 1, equation A) [44–47] and C-X coupling
reactions [48–50], we revisited tandem C-N/C-S bond forma-
tion to synthesize imidazobenzothiazines from 2-mercapto-
benzimidazole and 2-iodobenzylbromide (Scheme 1, equation
B) [34], and discovered the transition-metal-free synthesis of
imidazobenzothiazines (Scheme 1, equation C).
X. Tu Á L. Zhou (&) Á Z. Li Á N. Lei Á Q. Zeng (&)
Institute of Green Catalysis and Synthesis, College of Materials
and Chemistry and Chemical Engineering, Chengdu University
of Technology, Chengdu 610059, China
e-mail: zhoulihong2012@cdut.cn
Q. Zeng
e-mail: qinglezeng@hotmail.com
123

1926
X. Tu et al.
Scheme 1
R1
R2
R2
CuI (0.3 mmol)
K2CO3 (5 mmol)
X1
X2
SH
S
R1
(A)
(B)
+
DMSO (5 cm3)
120 oC, 48 h
NH2
N
H
R2
CuI (10 mol%)
L-Proline (10 mol%)
Cs2CO3 4.0 eq.
H
N
R2
X
R1
1
R
SH +
N
DMF, 120 oC
N2, 20 h
Br
N
S
N
R2
H
R2
N
X
Cs2CO3 2.0 eq.
(C) R1
R1
SH
+
N
DMF, 140 oC
Argon, 18 h
This work
Br
N
S
N
Results and discussion
up to 83 % (Table 1, entry 19). But the yield did not
increase any more when temperature was further raised to
150 °C (Table 1, entries 19 and 20). Both shortening and
prolonging reaction time gave no positive effect on the
yields (Table 1, entries 21 and 22).
As a start, we choose 2-mercaptobenzimidazole and
2-iodobenzyl bromide as the model substrates to opti-
mize reaction conditions, and the results are summarized
in Table 1.
With the optimized conditions at hand, other substrates
were evaluated to examine the scope of the transition-
metal-free C-S/C-N tandem reaction (Table 2). The results
showed that all of the tested 2-mercaptobenzimidazoles
could react with 2-halobenzyl bromides smoothly with
good to excellent yields (Table 2). When 5-methyl-1H-
benzo[d]imidazole-2-thiol was used, a pair of isomers of
imidazobenzothiazine with 9- and 10-methyl groups was
obtained with an excellent total yield of 90 % and with
nearly 1:1 isomer ratio (Table 2, entry 2). All of the
substituted 1H-benzo[d]imidazole-2-thiols 1 (5-Me, Cl,
EtO, MeO, CF3, and NO2) afforded a pair of isomers with a
ratio of about 1:1, respectively (Table 2, entries 2–7).
Furthermore, we noticed that 1H-benzo[d]imidazole-2-
thiol with electron-withdrawing groups gave lower yield
(Table 2, entries 6 and 7), while these with electron-
donating groups afforded higher yields (Table 2, entries
2–5).
Firstly, we performed the reaction under the similar
reaction conditions to the coupling reactions [44]. The
expected product was obtained with high yield up to 85 %
(Table 1, entry 1). CuBr, CuCl, Cu(OAc)2, CuO, and
CuSO4 were found to be efficient catalysts for the tandem
C-S/C-N reactions, while CuI gave the best result (Table 1,
entries 1–7). In view of recent advances in transition-metal-
free reactions [4–15], we intentionally performed this
reaction without any copper salt as catalyst, and we sur-
prisingly found that the desired product was also obtained
(Table 1, entry 8). We then changed K2CO3 to Na2CO3,
but lower yield was encountered (Table 1, entry 9).
In account of the hydrogen atoms attaching to S and N
are acidic rather than basic, we surmised that more basic
base may benefit this reaction. So we tried K3PO4, KOH,
and NaOH (Table 1, entries 10–12); however, the yield
decreased. Fortunately, when we tried Cs2CO3 as a base,
the yield increased to 52 % (Table 1, entry 13). After
screening the amount of Cs2CO3, 2.0 equivalents were
found to be the best one for this reaction (Table 1, entries
13–15).
On the contrary to the effects of electronic properties of
substituents in 1H-benzo[d]imidazole-2-thiols on yields,
2-bromobenzyl bromide with an electron-withdrawing tri-
fluoromethyl group reacted with 2-mercaptobenzimi-
dazoles to afford pretty good yields (Table 2, entries 8–11).
These 2-halobenzyl bromides with electron-donating
groups (4,5-OCH2O and 5-OCH3) gave lower yields, no
matter whether the substituents on 1H-benzo[d]imidazole-
Next, we studied the solvent influence. When performed
in DMA, the yield went up to 54 %, and peaked in DMF at
57 % (entries 16, 17, and 18 vs. 13). We next increased the
reaction temperature to 140 °C, and the yield sharply rose
123

Transition-metal-free synthesis of imidazobenzothiazines
1927
2-mercaptobenzimidazole (1.0 mmol) to make clear which H
atom attached to S and N atoms in 2-mercaptobenzimidazole
was first deprotonated by Cs2CO3. The result of only the C-S
formation product obtained (Scheme 2, equation A), which
implies that Cs2CO3 first deprotonates the S-attached H atom.
To figure out which carbon atom (C2 of the aromatic ring
or benzylic carbon) is first to react with S or N heteroatom,
we performed the reaction of 2-mercaptobenzimidazole
(1.0 mmol) with benzyl bromide (1.0 mmol) and iodoben-
zene (1.0 mmol). That the only product 2-(benzylthio)-1H-
benzo[d]imidazole was obtained demonstrates that the ben-
zylic carbon was the first to react with thio group (Scheme 2,
equation B). So the C-S bond is formed via a SN2 pathway
with the aid of Cs2CO3, and then an intramolecular nucleo-
philic aromatic substitution (SNAr) affords the desired
product.
Table 1 Optimization of reaction conditions
H
I
N
Conditions
SH
N
+
Br
N
S
2
1
3
Entry Catalyst
Base
Solvent T/°C t/h Yield/%a
1
CuI
K2CO3
K2CO3
K2CO3
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
120
140
150
140
140
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
18
12
24
85
82
84
81
82
82
83
47
31
38
35
35
52
46
48
43
54
57
83
82
74
82
2
CuBr
CuCl
3
4
Cu(OAc)2 K2CO3
5
CuO
K2CO3
K2CO3
K2CO3
K2CO3
6
CuSO4
7
Cu
–
–
–
–
–
–
–
–
–
–
–
–
–
–
–
8
Based on the above experimental data, a mechanism is
proposed (Scheme 3). The first step is the double molecular
nucleophilic substitution (SN2) of 2-mercaptobenzimidazole
and 2-iodobenzyl bromide with the aid of Cs2CO3. Then a
small amount of S-(2-iodobenzylthio)benzimidazole is
deprotonated by Cs2CO3 and the resulting strong benzoim-
idazole anion attacks iodobenzene via intramolecular SNAr
mechanism to afford the desired imidazobenzothiazines. The
higher temperature and intramolecular proper spatial struc-
ture are necessary factors for this transformation.
9
Na2CO3 DMSO
10
11
12
13
14b
15c
16
17
18
19
20
21
22
K3PO4
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
KOH
NaOH
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMA
DMF
In conclusion, the first transition-metal-free domino
C-S/C-N formation for the synthesis of imidazobenzothi-
azines from readily available 2-halobenzyl halides and
2-mercaptobenzimidazoles has been developed. The imi-
dazobenzothiazines have potential application in
biologically active compounds and functional material
additives, so the facile cascade process without residual
transition metal contamination has a good prospect in
pharmaceutics and functional materials.
DMF
DMF
DMF
DMF
Reaction conditions: unless otherwise noted, all these cascade cou-
plings were performed with 2.0 equiv. base under argon
a
Yield after isolation
b
Cs2CO3 was used in 1.0 equiv.
c
Cs2CO3 was used in 3.0 equiv.
Experimental
2-thiol were electron-donating or withdrawing (Table 2,
entries 12–16). All of the reactions of substituted 1H-
benzo[d]imidazole-2-thiols with 2-bromobenzyl bromides
provided pairs of isomers (Table 2, entries 9–15). Lower
yield encountered when 2,6-dichlorobenzyl bromide was
used as a substrate (Table 2, entry 17). The reason proba-
bly is the lower activity of chloro atom on the aromatic
ring. The simple 1H-imidazole-2-thiol also reacted
smoothly with 2-iodobenzyl bromide but gave moderate
yield (Table 2, entry 18).
All the reagents were purchased from Aldrich, Alfa Aesar,
Aladdin, and Kelong chemical companies and used without
further purification. KOH (99.999 %, metals basis), NaOH
(99.99 %, metals basis), Na2CO3 (99.9999 %, metals
basis), and K2CO3 (99.995 %, metals basis) were pur-
chased from Aladdin Reagent Company and Cs2CO3 with a
purity of 99.994 % (metals basis) was purchased from Alfa
Aesar Company.
Purification of the synthesized compounds was carried
Next, to explore the transition-metal-free tandem C-S/C-N
reaction mechanism, the following control experiments were
performed under the standard reaction conditions. We first
chose benzyl bromide (1.0 mmol) to couple with
out by flash column chromatography with silica gel
1
(300–400 meshes). H NMR and 13C NMR spectra were
recorded with DMSO-d6 or CDCl3 as solvent and TMS as
an internal standard on a Bruker Avance-300 or 400
123

1928
X. Tu et al.
Table 2 C-S/C-N tandem reaction of 2-mercaptobenzimidazoles with 2-halobenzyl bromides under optimized conditions
R2
R1
R1
R2
H
N
X
Cs2CO3 2.0 eq.
DMF, 140 o
+
SH
N
Br
C
N
S
Argon, 18 h
1
2
3
Entry
R1
R2
X
Product
Yield/%a
1
H
H
H
H
H
H
H
H
I
3a
3b
3c
3d
3e
3f
83
90
85
88
79
72
61
87
92
90
91
74
75
78
67
77
70
66
2
5-Me
5-Cl
5-EtO
5-MeO
5-CF3
5-NO2
H
I
3
I
4
I
5
I
6
I
7
I
3g
3h
3i
8b
9b
10b
11b
12
13
14
15
16
17
18c
5-CF3
5-CF3
5-CF3
5-CF3
Br
Br
Br
Br
Br
Br
Br
Br
Br
Cl
I
5-Me
5-Cl
5-EtO
5-Me
5-Cl
5-EtO
5-MeO
H
3j
3k
3l
4,5-OCH2O
4,5-OCH2O
4,5-OCH2O
4,5-OCH2O
5-OCH3
6-Cl
3m
3n
3o
3p
3q
3r
H
–
H
Reaction conditions: unless otherwise noted, all these cascade couplings were performed with 2.0 equiv. of base under argon protection
a
Yield after isolation
b
1.0 equiv. Cs2CO3 was used
c
3.0 equiv. Cs2CO3 was used, starting material was 2-mercaptoimidazoline
Scheme 2
S
N
H
Cs2CO3 2.0 eq.
N
HN
+
SH
(A)
(B)
DMF, 140 oC
Argon, 18 h
Br
N
Isolated yield: 87%
S
N
H
N
I
Cs2CO3 2.0 eq.
HN
+
+
SH
DMF, 140 oC
Argon, 18 h
Br
N
Isolated yield: 87%
spectrometer (300 MHz, 400 MHz). All IR spectra were
taken on a Bruker Tensor-27 infrared spectrometer with an
OPUS workstation. Electrospray ionization mass spectra
were recorded on an Agilent 1200 series LC/MS DVL
instrument. Melting points were determined on an X-4
melting-point apparatus with microscope.
123

Transition-metal-free synthesis of imidazobenzothiazines
1929
Scheme 3
I
Br
H
S
H
N
N
N
Cs2CO3
SH
S
Cs
NH
I
- CsHCO3
N
SN2
- CsBr
N
S
S
I
N
N
Cs2CO3
SNAr
- CsI
N
N
140 oC
- CsHCO3
Cs
General procedure for C-S/C-N one-pot tandem
reaction: 5H-benzimidazo[1,2-a][3, 1]-
benzothiazine (3a)
(dd, J = 19.9, 5.3 Hz, 1H), 7.58 (d, J = 7.4 Hz, 1H), 7.53
(d, J = 7.9 Hz, 1H), 7.37 (t, J = 5.5 Hz, 1H), 7.33 (d,
J = 1.9 Hz, 1H), 4.31 (d, J = 3.1 Hz, 2H) ppm; 13C NMR
(75 MHz, DMSO): d = 152.22, 151.50, 144.36, 142.15,
134.32, 132.78, 131.06, 129.12, 128.37, 127.57, 126.13,
123.50, 122.84, 119.81, 118.22, 113.14, 111.77,
29.02 ppm; MS (ESI): m/z = 273 ([M ? H]?).
To an oven-dried test tube with ground joint with a mag-
netic stir bar, 150 mg 2-mercaptobenzimidazole
(1.0 mmol), 650 mg Cs2CO3 (2.0 mmol), 297 mg 2-iod-
obenzyl bromide (1.0 mmol), and 5 cm3 DMF were added.
Then the sealed test tube was evacuated and backfilled with
argon for three times. The test tube was put in a preheated
oil bath at 140 °C, and the mixture was stirred at 140 °C
for 18 h (see Table 2). After the test tube was cooled to
room temperature, it was unfastened and 10 cm3 water was
added. The reaction mixture was extracted with 15 cm3
ethyl acetate for three times. The combined organic layer
was dried over anhydrous Na2SO4 and condensed in vacuo.
The residue was purified by column chromatography on
silica gel with petroleum ether and ethyl acetate (10:1 to
3:1 v/v) as an eluent to provide the desired product.
9- and 10-Ethoxy-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine, mixture of isomers (3d, C16H14N2OS)
Yield: 88 %; light yellow solid; m.p.: 112–113 °C; 1H NMR
(300 MHz, CDCl3): d = 7.81 (d, J = 8.1 Hz, 1H), 7.61 (d,
J = 8.8 Hz, 1H), 7.45 (t, J = 7.8 Hz, 1H), 7.39 (d,
J = 6.9 Hz, 1H), 7.32 (d, J = 2.2 Hz, 1H), 7.26 (dd,
J = 8.0, 7.0 Hz, 1H), 6.94 (dd, J = 8.8, 2.3 Hz, 1H), 4.10
(q, J = 7.0 Hz, 2H), 4.01 (s, 2H), 1.46 (t, J = 7.0 Hz, 3H)
ppm; 13C NMR (101 MHz, CDCl3): d = 155.99, 150.64,
148.99, 144.90, 38.29, 135.39, 133.16, 128.85, 128.09,
125.67, 119.63, 117.78, 112.55, 111.79, 102.95, 97.25,
64.35, 30.52, 14.93 ppm; MS (ESI): m/z = 283 ([M ? H]?).
5H-Benzimidazo[1,2-a][3, 1]-
9- and 10-Methoxy-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine (3a, C14H10N2S)
benzothiazine, mixture of isomers (3e, C15H12N2OS)
Yield: 79 %; yellow oil; 1H NMR (300 MHz, CDCl3):
d = 7.48 (d, J = 1.5 Hz, 1H), 7.38 (dd, J = 11.6, 4.8 Hz,
1H), 7.30 (t, J = 6.6 Hz, 3H), 7.21 (m, 1H), 7.13 (d,
J = 1.4 Hz, 1H), 3.99 (s, 3H) ppm; 13C NMR (101 MHz,
CDCl3): d = 143.48, 140.55, 132.51, 132.16, 128.06,
127.04, 121.28, 119.31, 118.43, 118.00, 37.83,
28.68 ppm; MS (ESI): m/z = 269 ([M ? H]?).
Yield: 83 %; bright yellow solid; m.p.: 112–114 °C;
1H NMR (400 MHz, CDCl3) dd = 7.83 (m, 2H), 7.75
(m, 1H), 7.46 (m, 2H), 7.32 (m, 2H), 7.27 (m, 1H), 4.04 (s,
2H) (Ref. [34] 112–113 °C).
9- and 10-Methyl-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine, mixture of isomers (3b, C15H12N2S)
Yield: 90 %; yellow oil; 1H NMR (300 MHz, CDCl3)
d = 7.78 (dd, J = 11.4 Hz, 8.2 Hz, 1H), 7.62 (dd, J = 12.0
Hz, 8.4 Hz, 1H), 7.48 (m, 1H), 7.41 (dd, J = 11.0 Hz, 4.4 Hz,
1H), 7.35 (d, J = 7.5, 1H), 7.22 (m, 1H), 7.11 (m, 1H), 3.98
9- and 10-(Trifluoromethyl)-5H-benzimidazo[1,2-a]-
[3, 1]benzothiazine, mixture of isomers
(3f, C15H9F3N2S)
1
(s, 2H), 2.49 (d, J = 10.9, 3H), H NMR was found to be
Yield: 72 %; light yellow solid; m.p.: 132–134 °C; 1H
NMR (300 MHz, CDCl3): d = 7.32 (d, J = 8.1 Hz, 1H),
7.17 (td, J = 7.8, 1.5 Hz, 1H), 7.04 (d, J = 7.3 Hz, 1H),
7.00 (s, 1H), 6.96 (d, J = 8.1 Hz, 1H), 6.85 (m, 2H), 6.28
(s, 1H), 4.05 (s, 2H) ppm; 13C NMR (101 MHz, CDCl3):
d = 143.38, 141.84, 132.85, 130.05, 129.60, 129.00,
identical with the one described in Ref. [34].
9- and 10-Chloro-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine, mixture of isomers (3c, C14H9ClN2S)
Yield: 85 %; white solid; m.p.: 157–158 °C; 1H NMR
(300 MHz, DMSO): d = 7.98 (m, 1H), 7.89 (m, 1H), 7.69
123

1930
X. Tu et al.
128.23, 127.64, 120.85, 119.69, 116.11, 115.63,
38.07 ppm; MS (ESI): m/z = 307 ([M ? H]?).
9- and 10-Ethoxy-3-(trifluoromethyl)-5H-benzimidazo-
[1,2-a][3, 1]benzothiazine, mixture of isomers
(3k, C17H13F3N2OS)
9- and 10-Nitro-5H-benzimidazo[1,2-a][3, 1]-
Yield: 91 %; white solid; m.p.: 165–168 °C; 1H NMR
(300 MHz, CDCl3): d = 7.92 (m, 1H), 7.67 (m, 3H), 7.23
(d, J = 2.3 Hz, 1H), 6.96 (m, 1H), 4.12 (m, 4H), 1.47 (td,
J = 7.0, 2.3 Hz, 3H) ppm; 13C NMR (75 MHz, CDCl3):
d = 156.37, 150.50, 148.66, 145.12, 138.30, 128.88,
127.78, 127.34, 126.74, 126.09, 125.19, 121.78, 119.99,
117.85, 113.02, 112.20, 111.66, 103.33, 97.42, 64.42,
64.04, 29.63, 14.79 ppm; MS (ESI): m/z = 351
([M ? H]?).
benzothiazine, mixture of isomers (3g, C14H9N3O2S)
Yield: 61 %; light yellow solid; m.p.: 214-216 °C; 1H
NMR (300 MHz, CDCl3) d = 8.74 (d, J = 2.0 Hz, 1H),
8.59 (d, J = 2.0 Hz, 1H), 8.25 (ddd, J = 8.9, 5.2, 2.2 Hz,
2H), 7.88 (d, J = 9.0 Hz, 1H), 7.80 (dd, J = 17.0, 8.5 Hz,
3H), 7.57 (m, 2H), 7.48 (d, J = 6.8 Hz, 2H), 7.38 (td,
J = 7.5, 1.7 Hz, 2H), 4.11 (d, J = 4.9 Hz, 4H) ppm; 13C
NMR (101 MHz, CDCl3): d = 152.27, 151.57, 144.82,
142.53, 135.10, 133.08, 131.25, 129.03, 128.27, 126.26,
125.71, 124.01, 123.25, 120.15, 119.60, 118.14, 111.70,
30.37 ppm; MS (ESI): m/z = 284 ([M ? H]?).
9- and 10-Methyl-5H-benzimidazo[1,2-a]-1,3-dioxolo-
[4,5-g][3, 1]benzothiazine, mixture of isomers
(3l, C16H12N2O2S)
Yield: 74 %; white solid; m.p.: 166–169 °C; 1H NMR
(300 MHz, CDCl3): d = 7.61 (d, J = 8.3 Hz, 1H), 7.51 (s,
1H), 7.36 (d, J = 9.2 Hz, 1H), 7.13 (dd, J = 8.3, 4.0 Hz,
1H), 6.86 (s, 1H), 6.03 (d, J = 4.0 Hz, 2H), 3.92 (d,
J = 2.0 Hz, 2H), 2.51 (d, J = 9.9 Hz, 3H) ppm; 13C NMR
(75 MHz, CDCl3): d = 147.84, 144.93, 143.90, 141.65,
132.95, 130.51, 129.81, 124.58, 124.11, 119.32, 118.93,
118.61, 110.94, 110.39, 107.92, 101.83, 100.23, 29.59,
21.82, 21.34 ppm; MS (ESI): m/z = 297 ([M ? H]?).
3-(Trifluoromethyl)-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine (3h, C15H9F3N2S)
Yield: 87 %; white solid; m.p.: 134–136 °C; 1H NMR
(300 MHz, CDCl3): d = 7.98 (d, J = 8.4 Hz, 1H), 7.80
(m, 1H), 7.77 (d, J = 1.6 Hz, 1H), 7.75 (m, 1H), 7.71 (s,
1H), 7.37 (m, 2H), 4.11 (s, 2H) ppm; 13C NMR (101 MHz,
CDCl3): d = 172.23, 154.63, 135.14, 133.83, 130.23,
129.36, 128.51, 126.38, 120.52, 117.17, 114.31, 77.36,
77.04, 76.72, 30.94 ppm; MS (ESI): m/z = 307
([M ? H]?).
9- and 10-Chloro-5H-benzimidazo[1,2-a]-1,3-dioxolo-
[4,5-g][3, 1]benzothiazine, mixture of isomers
(3m, C15H9ClN2O2S)
9- and 10-Methyl-3-(trifluoromethyl)-5H-benzimidazo-
[1,2-a][3, 1]benzothiazine, mixture of isomers
(3i, C16H11F3N2S)
Yield: 75 %; white solid; m.p.: 196–198 °C; 1H NMR
(300 MHz, CDCl3): d = 7.71 (dd, J = 8.4, 1.9 Hz, 1H),
7.63 (dd, J = 8.6, 3.0 Hz, 1H), 7.29 (dd, J = 5.0, 2.5 Hz,
1H), 7.25 (d, J = 2.1 Hz, 1H), 6.87 (s, 1H), 6.07 (d,
J = 3.4 Hz, 2H), 3.95 (d, J = 1.0 Hz, 2H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 152.15, 151.45, 147.56, 145.07,
144.01, 141.80, 132.69, 130.96, 128.56, 127.48, 123.30,
122.70, 119.66, 119.35, 118.04, 112.95, 111.57, 108.22,
102.02, 100.60, 100.29, 29.28 ppm; MS (ESI): m/z = 317
([M ? H]?).
Yield: 92 %; light yellow solid; m.p.: 174–176 °C; 1H
NMR (300 MHz, CDCl3): d = 7.95 (m, 1H), 7.74 (t,
J = 7.2 Hz, 1H), 7.68 (d, J = 6.2 Hz, 1H), 7.63 (d,
J = 7.4 Hz, 1H), 7.56 (d, J = 14.0 Hz, 1H), 7.17 (dd,
J = 7.3, 5.1 Hz, 1H), 4.08 (s, 2H), 2.51 (d, J = 11.1 Hz,
3H) ppm; 13C NMR (75 MHz, CDCl3): d = 150.18,
149.52, 144.34, 142.09, 138.14, 133.89, 133.60, 132.61,
130.44, 126.13, 125.09, 124.58, 119.70, 119.17, 118.09,
111.41, 110.82, 29.64 ppm; MS (ESI): m/z = 321
([M ? H]?).
9- and 10-Ethoxy-5H-benzimidazo[1,2-a]-1,3-dioxolo-
[4,5-g][3, 1]benzothiazine, mixture of isomers
9- and 10-Chloro-3-(trifluoromethyl)-5H-benzimidazo-
[1,2-a][3, 1]benzothiazine, mixture of isomers
(3n, C17H14N2O3S)
Yield: 75 %; white solid; m.p.: 217–220 °C; 1H NMR
(300 MHz, CDCl3) d = 7.60 (dd, J = 8.8, 1.5 Hz, 1H),
7.25 (m, 2H), 6.93 (m, 1H), 6.86 (d, J = 2.2 Hz, 1H), 6.05
(d, J = 2.4 Hz, 2H), 4.11 (m, 2H), 3.93 (d, J = 1.7 Hz,
2H), 1.46 (td, J = 7.0, 2.2 Hz, 3H) ppm; 13C NMR
(75 MHz, DMSO-d6): d = 155.93, 147.95, 145.03, 144.61,
138.08, 133.07, 129.79, 119.71, 112.59, 111.48, 108.01,
103.01, 101.90, 100.10, 96.86, 64.21, 29.27, 14.86 ppm;
MS (ESI): m/z = 327 ([M ? H]?).
(3j, C15H8ClF3N2S)
Yield: 90 %; white solid; m.p.: 184–186 °C; 1H NMR
(300 MHz, CDCl3): d = 7.89 (q, 1H), 7.78 (d, J = 2.0 Hz,
1H), 7.72 (t, J = 5.1 Hz, 2H), 7.66 (m, 1H), 7.32 (m, 1H),
4.11 (s, 2H) ppm; 13C NMR (75 MHz, CDCl3):
d = 151.61, 144.91, 142.59, 137.64, 132.85, 131.00,
129.50, 126.23, 125.37, 124.55, 123.67, 120.40, 119.60,
118.13, 111.90, 111.51, 77.41, 76.98, 76.56, 29.64 ppm;
MS (ESI): m/z = 341 ([M ? H]?).
123

Transition-metal-free synthesis of imidazobenzothiazines
1931
14. Zhao J, Zhao Y, Fu H (2011) Angew Chem Int Ed 50:3769
´
9- and 10-Methoxy-5H-benzimidazo[1,2-a]-1,3-dioxolo-
[4,5-g][3, 1]benzothiazine, mixture of isomers
(3o, C16H12N2O3S)
15. Thome I, Besson C, Kleine T, Bolm C (2013) Angew Chem Int
Ed 52:7509
16. Lazer ES, Matteo MR, Possanza GJ (1987) J Med Chem 30:726
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(2009) Arch Pharm Chem Life Sci 342:230
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Sci 11:311
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Joubran C, Abedi JK, Jones J, Ku¨hler TC (2002) J Med Chem
45:4300
20. Sivakumar PM, Babu SKG, Doble M (2008) Chem Biol Drug
Des 71:447
1
Yield: 67 %; bright yellow crystals; m.p.: 96–98 °C; H
NMR (300 MHz, CDCl3): d = 7.36 (d, J = 1.4 Hz, 1H),
7.10 (t, J = 3.3 Hz, 2H), 6.79 (d, J = 14.2 Hz, 2H), 6.01
(s, 2H), 5.91 (s, 1H), 4.22 (s, 1H), 3.90 (s, 3H) ppm; 13C
NMR (75 MHz, DMSO-d6): d = 148.60, 147.24, 146.95,
138.74, 134.56, 127.46, 116.67, 112.01, 108.15, 101.80,
62.56, 18.12 ppm; MS (ESI): m/z = 313 ([M ? H]?).
21. Vasan M, Neres J, Williams J, Wilson DJ, Teitelbaum AM,
Remmel RP, Aldrich CC (2010) Chem Med Chem 5:2079
22. Setyan A, Sauvain J-J, Guillemin M, Riediker M, Demirdjian B,
Rossi MJ (2010) Chem Phys Chem 11:3823
3-Methoxy-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine (3p)
Yield: 77 %; bright white solid; m.p.: 102–104 °C (Ref.
[34] 102-103 °C).
23. Shukla JS, Singh HH, Parmar SS (1969) J Prakt Chem 311:187
´
24. Clement M-J, Krishnan R, Elisabeth A, Flavio T, Curmi PA,
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25. Bauer J, Kinast S, Burger-Kentischer A, Finkelmeier D, Kley-
4-Chloro-5H-benzimidazo[1,2-a][3, 1]-
benzothiazine (3q, C14H9ClN2S)
Yield: 70 %; bright white solid; m.p.: 166–167 °C; 1H
NMR (300 MHz, CDCl3): d = 7.75 (dd, J = 1.9, 3.6 Hz,
3H), 7.43-7.28 (m, 4H), 4.25 (s, 2H) ppm; 13C NMR
(75 MHz, CDCl3): d = 150.57, 144.03, 136.78, 132.89,
129.11, 126.70, 124.46, 123.70, 123.18, 119.65, 116.75,
111.33, 26.79 ppm; MS (ESI): m/z = 273 ([M ? H]?).
¨
¨
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5H-Imidazo[1,2-a][3,1]benzothiazine (3r)
Yield: 66 %; yellow oil; 1H NMR was found to be identical
with the one described in Ref. [34].
2-(Benzylthio)-1H-benzimidazole (3s)
Yield: 61 %; white solid; m.p.: 183–185 °C (Ref. [51]
184–185 °C).
Acknowledgments We thank the National Natural Science Foun-
dation of China (No. 21372034) and the cultivating program for
excellent innovation team of Chengdu University of Technology.
38. Bao W, Liu Y, Lv X, Qian W (2008) Org Lett 10:3899
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123