Imidazobenzothiazine and primidobenzothiazine derivatives synthesis via an aliphatic SN2 substitution/Cu(I) catalyzed Ullmann coupling cascade process

Article abstract of DOI:10.1016/j.tetlet.2011.11.072

An efficient method for the preparation of various imidazobenzothiazine and primidobenzothiazine derivatives from readily available 2-mercaptoimidazoles (thiouracils) and bromobenzyl bromides via a copper(I)-catalyzed one-pot cascade process has been deve

Full text of DOI:10.1016/j.tetlet.2011.11.072

Tetrahedron Letters 53 (2012) 442–445
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Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Imidazobenzothiazine and primidobenzothiazine derivatives synthesis via an
aliphatic SN2 substitution/Cu(I) catalyzed Ullmann coupling cascade process
⇑
⇑
Ruihong Wang, Weixing Qian , Weiliang Bao
Department of Chemistry, Xi Xi Campus, Zhejiang University, Hangzhou, Zhejiang 310028, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the preparation of various imidazobenzothiazine and primidobenzothiazine
derivatives from readily available 2-mercaptoimidazoles (thiouracils) and bromobenzyl bromides via a
copper(I)-catalyzed one-pot cascade process has been developed. The reaction involves a SN2 process
and an intramolecular C–N cross coupling cyclization.
Received 10 August 2011
Revised 21 October 2011
Accepted 15 November 2011
Available online 19 November 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Copper(I) catalysis
Imidazobenzothiazine derivatives
Intramolecular C–N cross coupling
2-Mercaptoimidazole
Cascade reactions
Nitrogen- and sulfur-containing heterocycles are ubiquitous
substructures in a huge number of biologically active natural prod-
ucts and small-molecule pharmaceuticals.1 Substituted 2-mercapto
benzimidazole molecules have drawn much attention of synthetic
chemists because of their broad range of biological activities such
as antimicrobial,2 antitubercular,3 antifungal,4 and antagonist.5
What is more, substituted 2-mercaptobenzimidazoles have been
utilized as metal corrosion inhibitor,6,7 rubber products antioxi-
dant,8 and heavy metal ions adsorbents.9 Compounds containing
5H-benzo[d]imidazo[2,1-b][1,3]thiazine structures have received
much attention in material, medicinal, and pharmaceutical
research, mainly due to their important biological activities and
structural advantages. For example, substituted 5H-benzo[d]
imidazo[2,1-b][1,3]thiazine (Fig. 1A and B) was reported possessing
antimicrobial activity.10 Polymer containing 5H-benzo[d]imidazo
[2,1-b][1,3]thiazine structure was found to be a silver halide color
photographic photosensitive material.11 Therefore the synthesis
of such compounds libraries should be interesting.
cyclization.13 These aforementioned synthetic routes might be lim-
ited owing to their narrow scopes, need to use very strong base or
special reagents, or the tedious multistep manipulation. Therefore,
concise and efficient methods to give these heterocyclic motifs are
still in demand.
In the past few years, the formation of aryl C–X bonds (X = N, O, S,
etc.) via copper-catalyzed Ullmann-type coupling between aryl ha-
lides and heteroatom-centered nucleophiles has made tremendous
progress.14 Morerecently, one-potstrategiesforthesynthesisofvar-
ious useful heterocyclic compounds based on the copper-catalyzed
C(aryl)–X (X = N, O, S, etc.) bond formation have been extensively
studied.15 Our group have endeavored designing and synthesizing
heterocycles via copper promoted cascade or domino one-pot
processes.16 We conjectured that the eye-drawing compound 2-
mercaptoimidazole might react with 2-bromobenzyl bromide via a
SN2 substitution/C–N coupling domino process. To the best of our
knowledge, there is no report about the formation of imidazobenzo-
thiazines via a one-pot copper-catalyzed coupling process.
However, only a few methods have been reported access to
imidazobenzothiazines, especially to benzimidazobenzothiazines.
Jean Gauthier and co-workers reported the synthesis of 5H-benzo
[d]imidazo[2,1-b][1,3]thiazines by condensation of 2-aminobenz-
hydrol with thiourea in three steps.12 Siegfried and co-workers also
reported the analogous compounds prepared in a similar way.10
Another approach to functionalized benzimidazobenzothiazines
was getting a precursor via a SN2 reaction and then adding NaH for
Initially, the readily available and inexpensive bromobenzyl
bromide (1a) and 2-mercaptobenzimidazole (2a) were selected as
a model substrate to optimize the reaction conditions, the results
are summarized in Table 1. The reaction was originally carried out
in CH3CN with CuI (10 mol %) as the catalyst, DMEDA (N,N0-dimeth-
ylethanediamine, 20 mol %) as the ligand and Cs2CO3 (4.0 equiv) as
the base at 110 °C under a N2 atmosphere. To our disappointment,
there is hardly any cyclization product (Table 1, entry 1). When
DMF was used as the solvent, benzimidazobenzothiazine was ob-
served, giving the yield of 52%. This result encouraged us to optimize
the reaction parameters to enhance the yield of 3a on this template
⇑
Corresponding authors. Fax: +86 571 88273814 (W.B.).
E-mail address: wlbao@css.zju.edu.cn (W. Bao).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.072

R. Wang et al. / Tetrahedron Letters 53 (2012) 442–445
NHAC
443
NHAC
s
s
O
O
MeO
N
N
OHC HNHN
O
O
N
N
R
N
O
N
S
N
N
S
S
O
A
B
C
O
Figure 1. Several 5H-benzo[d]imidazo[2,1-b][1,3]thiazine derivatives reported as biologically active compounds and photosensitive material.
Table 1
Optimization of the reaction conditionsa
S
N
N
Copper(I)/L, Base, N
o
Br
2
N
SH
+
Solvent, 110 C, 20 h
N
H
Br
1a
2a
3a
Entry
Copper(I)
Ligand
Base
Solvent
Yieldb (%)
1
2
3
4
CuI
CuI
CuI 15%
CuI
DMEDA L1
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
CH3CN
DMF
DMF
Trace
52
L1
L1
L1
51
DMF
20c
N
CO H
5
CuI
Cs2CO3
DMF
DMF
75
30
2
L2
6
CuI
Cs2CO3
N
N
L3
O
O
OEt
7
CuI
Cs2CO3
DMF
74
L4
8
9
CuI
CuI
Cs2CO3
Cs2CO3
DMF
DMF
82
68
L
-Proline L5
-Glutamic Acid L6
L
10
11
12
CuI
CuI
CuI
Diethylamine L7
Leucine L8
Cs2CO3
Cs2CO3
Cs2CO3
DMF
DMF
DMF
50
55
72
L
-Histidine L9
13
14
15
16
17
18
19
20
CuBr
CuCl
Cu(OTf)2
CuI
—
CuI
L5
L5
L5
—
L5
L5
L4
L5
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
DMF
DMF
DMF
DMF
DMF
Xylene
DMF
DMF
77
58
79
27
n.d.d
22
Cu2O
CuI
66
63
a
Reagents and conditions: 1a (0.5 mmol), 2a (0.5 mmol), copper source (0.05 mmol), ligand (0.1 mmol), and base (1.5–2.0 mmol, 3.0–4.0 equiv), solvent (2.0 mL), under N2
at 110 °C for 20 h.
b
Isolated yield.
The reaction temperature was 80 °C.
n.d.: not detected.
c
d
reaction. Adding 5 mol % more CuI did not improve the productivity.
While decreasing the reaction temperature gave an obviously lower
yield (Table 1, entry 4). Then, the influence of ligands was investi-
gated while other conditions were settled. Some typical ligands fre-
quently used for Cu-catalyzed coupling reactions have been
the optimized conditions were to use a combination of CuI
(10 mol %) and -Proline (20 mol %) in the presence of Cs2CO3
(4.0 equiv) as base in DMF.
L
With the optimal conditions established, we then tried to
explore the scope of this methodology (Table 2). Firstly, the reac-
tions of 2a with various substituted 2-bromobenzyl bromides were
examined (Table 2, entries 1–5). Both electron-rich (5-Me, 5-OMe)
and electron-deficient (4-Cl, 4-F, 5-Cl) substrates worked well,
giving the corresponding benzimidazobenzothiazines in good
yields (Table 2, entries 1–5). 5-Methyl-2-iodobenzyl bromide is
also a good substrate (Table 2, entry 5).
screened. Among the nine selected candidates, L-Proline was the
best one and L4 was the second (Table 1, entries 2, 4–12). Several
copper(I) salts have also been tested, it is turned out that CuI was
the most suitable catalyst (Table 1, entries 13–15). Cu2O was also
good considering inexpensive cost (Table 1, entry 19). Copper(II) salt
Cu(OTf)2 was also effective. Anticipated product was observed with-
out a ligand, though the yield was low (Table 1, entry 16). However
the reaction did not proceed in the absence of copper catalyst (entry
17). Non-polar solvent was less suitable for this process. Therefore,
To expand the scope of the reaction, we further examined the
mono- and disubstituted 2-mercaptoimidazole or disubstituted
2-mercaptobenzimidazole (Table 2, entries 7–17). The substituents

444
R. Wang et al. / Tetrahedron Letters 53 (2012) 442–445
Table 2
CuI-catalyzed one-pot synthesis of imidazobenzothiazine derivatives from substituted 2-bromobenzyl bromides and 2-mercaptoimidazolesa
S
N
CuI/L-Proline, Cs CO
2
3
N
Br
1
R
N
SH
+
o
DMF, 110 C, 20 h
N
H
Br
1
R
1
2
3
entry 4:
S
entry 3:
entry 1:
S
entry 2:
S
S
N
N
N
N
N
N
N
N
MeO
Cl
Cl
3a 82%
3b 67%
3c 63%
3d 76%
entry 5:
S
entry 7:
+
entry 6:
S
S
S
N
N
N
N
N
N
N
N
4g
3g
F
b
92% totally (1:1)
entry 9:
3e 82%
3f 87%
entry 8:
S
S
N
S
S
N
N
N
N
N
+
N
N
+
MeO
Cl
Cl
MeO
3h
4h
b
3i
4i
b
46% totally (1:1)
entry 11:
91% totally (1:1)
entry 13:
entry 12:
entry 14:
entry 10:
MeO
Cl
S
N
S
S
N
S
S
Cl
N
N
N
N
N
N
N
N
3j 66%
3m 77%
entry 18:
3n 82%
entry 19:
3l 63%
entry 17:
S
3k 92%
entry 16:
entry 15:
S
S
Cl
N
S
N
S
Ph
F
N
N
N
F
N
d
N
F
N
N
N
Ph
O
O
Ph
3p 93%
Ph
F
c
c
d
3r 80%
3q 95%
3s 81%
3o 89%
a
b
c
Reaction conditions: 1 (0.5 mmol), 2 (0.5 mmol), CuI (0.05 mmol), L-Proline (0.1 mmol) and Cs2CO3 (1.5–2.0 mmol, 3.0–4.0 equiv) in DMF (2.0 mL), under N2 at 110 °C for 20 h.
The ratios for 3g and 4g, 3h and 4h as well as 3i and 4i were obtained from the NMR.
The reaction time was 12 h.
t-BuOK was used as the base.
d
showed more remarkable effect in comparison with 2-bromoben-
zyl bromides (Table 2, entry 4, 9, 13, and 16). 2-mercaptoimidazole
with stronger electron-donating group proved giving higher yield
(Table 2, entry 16). It should be mentioned that we got the mixed
products for the two same conjugate sites when 2-mercapto-5-
methylbenzimidazole was used (Table 2, entries 7–9). Other simi-
lar structure motifs may also be coupled with 2-bromobenzyl bro-
mides to give more versatile heterocycles. When thiouracils were
used as substrates, primido-incorporated benzothiazines were ob-
tained in moderate yields (Table 2, entries 18 and 19).
S
N
N
Br
Copper(I)/L, Base
2
R
1
N
SH
+
R
Solvent
N
H
Br
1
R
2
R
1
2
3
S
N
B
a
b
HN
Br
2
BH
R
1
R
Scheme 1. Proposed process of one-pot synthesis of imidazobenzothiazine derivatives.

R. Wang et al. / Tetrahedron Letters 53 (2012) 442–445
445
O
References and notes
S
S
N
1.0 eq PhI(OAc)2
DMF, 50 C
N
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On the basis of these observations, the possible process is pro-
posed in Scheme 1. Firstly, the base abstracted a proton from 2 and
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mediate underwent an intramolecular C–N bond coupling in a Cu(I)/
ligand/base system. To our delight the proposed intermediate 6a
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system giving the same desired product 3a. The procedure also con-
firmed the structure of 3a. The possibility of CH2Br–HN SN2/(sp2)C–S
coupling cascade reaction product was ruled out.
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In conclusion, synthesis of imidazobenzothiazine and primi-
dobenzothiazine derivatives by the approach of aliphatic SN2 substi-
tution/Cu(I) catalyzed Ullmann coupling cascade process has been
developed. The efficiency and substituent tolerance of this proce-
dure have been fully demonstrated by the data in Tables 1 and 2.
Acknowledgment
This work was financially supported by the Natural Science
Foundation of China (No. 21072168).
Supplementary data
17. (a) Dalal, D. S.; Pawar, N. S.; Mahulikar, P. P. OPPI 2005, 6, 540; (b) Klimešová,
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.072.
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