Generation of 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides via a reaction of trifluoromethanesulfanylamide with 2-(2-alkynyl)benzenesulfonamide

Article abstract of DOI:10.1039/c3cc44263b

The incorporation of the (trifluoromethyl)thio group into the benzo[e][1,2]thiazine 1,1-dioxide scaffold via a reaction of trifluoromethanesulfanylamide with 2-(2-alkynyl)benzenesulfonamide is reported. The transformation proceeds under mild conditions to afford the 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides in moderate to good yields.

Full text of DOI:10.1039/c3cc44263b

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Generation of 4-((trifluoromethyl)thio)-2H-
benzo[e][1,2]thiazine 1,1-dioxides via a reaction
of trifluoromethanesulfanylamide with
2-(2-alkynyl)benzenesulfonamide†
Cite this: Chem. Commun., 2013,
49, 8647
Received 6th June 2013,
Accepted 27th July 2013
Qing Xiao,a Jie Sheng,b Zhiyuan Chen*a and Jie Wu*bc
DOI: 10.1039/c3cc44263b
www.rsc.org/chemcomm
The incorporation of the (trifluoromethyl)thio group into the
benzo[e][1,2]thiazine 1,1-dioxide scaffold via a reaction of trifluoro-
methanesulfanylamide with 2-(2-alkynyl)benzenesulfonamide is
reported. The transformation proceeds under mild conditions to afford
the 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides
in moderate to good yields.
It is well known that more than 20% of commercial drugs
contain fluorine. Additionally, the incorporation of fluorine
into drugs or leading compounds often results in a significant
improvement of their medicinal properties.1 Therefore, conti-
nuous efforts have been made for the generation of fluorinated
heterocycles.2 Recently, the introduction of the (trifluoromethyl)thio
Fig. 1 Benzo[e][1,2]thiazine 1,1-dioxide.
moiety (SCF3) into small molecules has attracted much attention we envisioned that the incorporation of the (trifluoromethyl)thio
due to its intrinsic properties, including its high lipophilicity.3 moiety into the scaffold of benzo[e][1,2]thiazine 1,1-dioxide
In the last few years, the important progress in this field has would be beneficial for the subsequent biological evaluations
been witnessed.4,5 Very recently, Billard highlighted the pro- (Fig. 1).
gress in the method development of C–SCF3 formation.5a
Recently, trifluoromethanesulfanylamide as an easy-to-handle
The core structure of benzo[e][1,2]thiazine 1,1-dioxide could equivalent of the trifluoromethanesulfanyl cation (CF3S+) has
be found in many natural products and pharmaceuticals with been used in the formation of C–SCF3 bonds.11 For instance,
remarkable biological activities.6,7 For example, ampiroxicam is Billard and co-workers explored the utility of trifluoromethane-
an anti-inflammatory and analgesic drug (Fig. 1, compound A).6 sulfanylamide in the reaction with alkenes and alkynes.11a
Compound B has been discovered as a calpain I inhibitor. Since Prompted by this result, we envisaged that it would be attractive
compounds with the (trifluoromethyl)thio moiety usually exhibit a if the 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides
high hydrophobicity parameter,8 they are consequently recognized could be constructed starting from the easily available trifluoro-
as important candidates in pharmaceutical and agrochemical methanesulfanylamide. We hypothesized that 2-(2-alkynyl)-
research.9 In light of our interest in the facile assembly of natural benzenesulfonamide could be involved in the reaction with
product-like compounds for the studies of chemical genetics,10 trifluoromethanesulfanylamide under suitable conditions. To
verify the feasibility of this hypothesis, we therefore started to
explore the possibility of this proposed transformation.
At the beginning, a model reaction of 2-(2-alkynyl)benzene-
sulfonamide 1a with trifluoromethanesulfanylamide 2 was studied
a Key Laboratory of Functional Small Organic Molecules, Ministry of Education and
College of Chemistry & Chemical Engineering, Jiangxi Normal University,
Nanchang, Jiangxi 330022, China
b Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433,
China. E-mail: jie_wu@fudan.edu.cn; Fax: +86 21 6564 1740;
Tel: +86 21 6510 2412
c Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, China
† Electronic supplementary information (ESI) available: Experimental procedure,
characterization data, 1H and 13C NMR spectra of compounds 3. See DOI:
10.1039/c3cc44263b
(Table 1). Initially, the reaction occurred at 80 1C in dichloroethane
(DCE). However, no reaction took place under the conditions
(Table 1, entry 1). Since arenesulfinamide could be utilized for
the electrophilic addition under Lewis acid activation,12 we
conceived that the presence of Lewis acid would induce the
electrophilic addition. Therefore, different metal salts were
screened. Only a trace amount of product was observed when
c
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Table 1 Initial studies for the reaction of 2-(2-alkynyl)benzenesulfonamide 1a
with trifluoromethanesulfanylamide 2
Table 2 Synthesis of 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides
through a reaction of 2-(2-alkynyl)benzenesulfonamide 1 with trifluoromethane-
sulfanylamide 2a
Entry
Lewis acid
T (1C)
Solvent
Yielda (%)
1
2
3
4
5
6
7
8
—
80
80
80
80
80
80
80
80
80
80
80
80
80
80
25
50
80
80
80
80
80
80
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
THF
n.d.
Trace
Trace
31
Trace
8
20
11
50
Trace
NR
NR
48
21
35
43
97
NR
NR
70
BF3ÁOEt2
In(OTf)3
InCl3
FeCl3
AgOTf
AgBF4
AgN(Tf)2
BiCl3
Bi(OTf)3
BiI3
Bi(OAc)3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
BiCl3
9
10
11
12
13b
14c
15
16
17d
18d
19d
20d
21d
22d
DMF
Toluene
MeCN
CHCl3
15
20
BiCl3
a
b
Isolated yield based on 2-(2-alkynyl)benzenesulfonamide 1a. In the
c
presence of 2.0 equivalent of BiCl3. In the presence of 0.5 equivalent of
BiCl3. In the presence of 3.0 equivalent of trifluoromethanesulfanyl-
d
amide 2.
BF3ÁOEt2 or In(OTf)3 was added in the reaction (Table 1, entries 2
and 3). To our delight, the desired product 3a was obtained in
31% yield when InCl3 was employed as a replacement (Table 1,
entry 4). However, the results were inferior when iron salts or
a
Isolated yield based on 2-(2-alkynyl)benzenesulfonamide 1.
silver salts were present (Table 1, entries 5–8). A better yield was 1,1-dioxide 3d could be obtained in 90% yield. It seemed that the
isolated when BiCl3 was used as the Lewis acid (Table 1, entry 9). substitution on the sulfonamide was crucial for the transforma-
However, the exact role of BiCl3 was uncertain. It seemed that the tion. No reaction occurred when 2-(2-alkynyl)benzenesulfonamide
anion played a key role in the reaction process, since the reaction 1 with a free amide group was employed in the reaction. The
failed to occur when Bi(OTf)3, BiI3, or Bi(OAc)3 was utilized substrate with a phenyl group attached to the sulfonamide
instead (Table 1, entries 10–12). The yield could not be improved also failed to furnish the expected product. The reactions of
when the amount of BiCl3 was increased (Table 1, entry 13). 2-(2-alkynyl)benzenesulfonamide 1 with different aryl groups
However, the yield was lower when 0.5 equivalent of BiCl3 attached onto the triple bond worked efficiently. However,
was employed or the temperature was decreased (Table 1, a lower yield (45%) was isolated when 2-(2-alkynyl)benzene-
entries 14–16). Gratifyingly, the desired product 3a was obtained sulfonamide 1 with a tert-butyl group attached to the alkynyl
in 97% yield when the reaction was performed in the presence of moiety was utilized in the reaction with trifluoromethane-
3.0 equivalents of trifluoromethanesulfanylamide 2 (Table 1, sulfanylamide 2. Interestingly, the substrate with an ester-
entry 17). We next shifted our focus on other solvents. The substituted phenyl group attached to the triple bond was
results disclosed that the reaction worked efficiently in DCE compatible under the standard conditions, which afforded
(Table 1, entries 18–22).
the desired product 3m in 52% yield. However, no reaction
We next explored the scope of the BiCl3-promoted reaction occurred when the substrate with an ester or hydroxyl group
of 2-(2-alkynyl)benzenesulfonamide 1 with trifluoromethane- attached to the triple bond was employed.
sulfanylamide 2 under the optimized conditions presented in
To our surprise, a 5-exo-cyclization adduct was observed
Table 1. The results are summarized in Table 2. In most cases, the when 2-(2-alkynyl)benzenesulfonamide 1 with an alkyl group
reaction proceeded smoothly to afford the corresponding products in attached to the triple bond was employed (Table 3). However,
good yield. The substituents on the aromatic ring of 2-(2-alkynyl)- the selectivity could be controlled by the electron effect. For
benzenesulfonamide 1 did not affect the final outcome. For instance, example, only a 6-endo-cyclization product was formed when
the chloro-substituted 4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine an electron-withdrawing group (chloro or trifluoromethyl) was
c
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Table 3 Scope investigation of the reaction of 2-(2-alkynyl)benzenesulfonamide 1
with trifluoromethanesulfanylamide 2a
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D. Bonnet-Delpon, Wiley, Hoboken, 2008.
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Yield (%)
Entry
R1
R2
3
4
1
2
3
4
5
6
7
8
Me
H
Cl
CF3
H
H
H
Cyclopropyl
Cyclopropyl
Cyclopropyl
Cyclopropyl
nBu
CH2CH2OCOEt
CH2CH2CH2Cl
CH2CH2CH2CN
23 (3n)
43 (3o)
52 (3p)
42 (3q)
38 (3r)
30 (3s)
45 (3t)
18 (3u)
61 (4a)
37 (4b)
0
0
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46 (4c)
40 (4d)
29 (4e)
45 (4f)
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Isolated yield based on 2-(2-alkynyl)benzenesulfonamide 1.
attached to the aromatic ring of 2-(2-alkynyl)benzenesulfonamide 1
(Table 3, entries 3 and 4).
In conclusion, we have reported an efficient synthesis of
4-((trifluoromethyl)thio)-2H-benzo[e][1,2]thiazine 1,1-dioxides
through a reaction of 2-(2-alkynyl)benzenesulfonamide with
trifluoromethanesulfanylamide. 2,3-Dihydrobenzo[d]isothiazole
1,1-dioxide could be formed as well in some cases. The presence
of BiCl3 was essential for a successful transformation. The
introduction of (trifluoromethyl)thio moiety (SCF3) into other
N-heterocycles is currently under exploration in our laboratory.
Financial support from the National Natural Science Founda-
tion of China (No. 21032007, 21172038) is gratefully acknowledged.
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´
c
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Chem. Commun., 2013, 49, 8647--8649 8649