Radical Route to 1,4-Benzothiazine Derivatives from 2-Aminobenzenethiols and Ketones under Transition-Metal-Free Conditions

Article abstract of DOI:10.1021/acs.orglett.6b03324

Transition-metal-free radical access to 1,4-benzothiazine derivatives from o-aminobenzenethiols is disclosed. This procedure is available for various ketones including α,β-unsaturated, cyclic, linear, and fluoroalkyl ketones to generate a number of 1,4-benzothiazines, which exist in numerous bioactive and natural molecules, rendering this protocol attractive to both synthetic and medicinal chemistry.

Full text of DOI:10.1021/acs.orglett.6b03324

Letter
pubs.acs.org/OrgLett
Radical Route to 1,4-Benzothiazine Derivatives from
2‑Aminobenzenethiols and Ketones under Transition-Metal-Free
Conditions
Ya-mei Lin, Guo-ping Lu,* Rong-kang Wang, and Wen-bin Yi*
Chemical Engineering College, Nanjing University of Science and Technology, Nanjing 210094, China
S
* Supporting Information
ABSTRACT: Transition-metal-free radical access to 1,4-
benzothiazine derivatives from o-aminobenzenethiols is dis-
closed. This procedure is available for various ketones including
α,β-unsaturated, cyclic, linear, and fluoroalkyl ketones to
generate a number of 1,4-benzothiazines, which exist in
numerous bioactive and natural molecules, rendering this
protocol attractive to both synthetic and medicinal chemistry.
Scheme 1. Transtion-Metal-Free Strategies for the
Generation of 1,4-Benzothiazines from 2-
Aminobenzenethiols and Ketones
rganosulfur heterocycles are known to represent a class
of important compounds because of their potential
O
biological activity, pharmaceutical significance, and synthetic
utility.1 Among them, 1,4-benzothiazines are considered the
core structures in many pharmaceutically active compounds
and natural products. In addition, they show a wide range of
biological activities in vivo and in vitro, such as antibacterial,
antidiabetic, anti-arrhythmic, and antitumor.2 Consequently,
the development of efficient approaches for the synthesis of 1,4-
benzothiazine derivatives is an appealing and valuable task to
both synthetic and medicinal chemistry.
Traditionally, these compounds are synthesized by transition-
metal-free condensation of o-aminobenzenethiols with β-
diketones or organic halides.3 Nevertheless, these strategies
suffer from the need for prepreparation of the starting materials,
narrow substrate scope, and poor regioselectivity. To solve
these issues, various transition-metal-catalyzed cross-coupling
reactions have been well-developed for the construction of 1,4-
benzothiazines.4,5 Although transition-metal-catalyzed cross-
couplings have proved to be very useful tools for the selective
formation of 1,4-benzothiazine derivatives, the use of toxic
transition-metal catalysts goes against the low threshold
residual tolerance of metals in pharmaceutical fields. Therefore,
the exploration of transition-metal-free strategies that have high
regioselectivity and broad substrate scope using cheap and easy-
to-handle substrates is still highly desirable.
On the one hand, Deng and co-workers reported the
selective formation of phenothiazine from 2-aminobenzene-
thiols and cyclohexanones using molecular oxygen as a
hydrogen acceptor under metal-free conditions at high
temperature (140 °C) (Scheme 1).6 On the other hand, thiyl
radicals as the center of some extremely efficient radical
reactions for the synthesis of organosulfur compounds7 may
have unique reactivity compared with sulfide cations and anions
in terms of electronic effects and substrate scope. Therefore, we
reasoned that the thiyl radical as the prior reaction center
would be a better option than the amino group because radical
substitution is easier than condensation.6,8 Along this line, here
we disclose the first example of radical access to various 1,4-
benzothiazine derivatives from 2-aminobenzenethiols and
ketones under transition-metal-free conditions (Scheme 1).
We started the investigation by selecting the reaction of 2-
aminobenzenethiol (1a) with chalcone (2a) as the model
reaction (Table 1). To our delight, the reaction provided a 61%
yield of the desired product 3a using Cs2CO3 as the base (entry
1). After screening of different amounts of the base, 0.5 equiv of
Cs2CO3 emerged as the best option (entries 1−4). In addition,
the types of solvent and base were also optimized in the
reaction, and the combination of methanol and Cs2CO3 was the
best choice (entry 8). The reaction was inhibited at lower
temperature (entry 15). No reaction took place in the absence
of base (entry 16). A poor yield was provided under an
atmosphere of N2, indicating that air is beneficial to the process
Received: November 6, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b03324
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Organic Letters
Letter
a
benzothiazines in moderate to excellent yields (3a−c).
Heterocyclic-substituted chalcones were also successfully
applied in the reaction with satisfactory results (3d−f). A
cyclic α,β-unsaturated ketone provided the corresponding
product 3j, presumably as a result of base-induced dehydrogen-
ation.10 The configuration of the final product remained unsure
when an alkyl α,β-unsaturated ketone was used (3g). In
addition, the reaction was sluggish when 2-aminoethane-1-thiol
was used (3i).
It should be noted that phenothiazines that were widely
employed in the design of various pharmaceuticals9 could also
be generated in this system by switching the substrates from
α,β-unsaturated ketones to cyclohexanones. DMSO proved to
be the best solvent, and base was not essential for this reaction.
Reactions of cyclohexanones occurred in moderate to good
yields (4a−e; Scheme 3). 2-Aminoethane-1-thiol was applied to
Table 1. Optimization of the Reaction Conditions
b
entry
base
x
solvent
DMSO
yield (%)
61
1
2
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
K2CO3
2
c
1
DMSO
DMSO
DMSO
H2O
65, 55
3
0.5
0.3
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0
60
41
nr
4
5
6
1,4-dioxane
DMF
40
42
7
d
8
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
91, 86
9
80
40
56
62
32
37
10
11
12
13
14
15
16
17
18
DBU
t-BuOK
NaOH
Scheme 3. Reaction of o-Aminobenzenethiols with Cyclic
a b
,
Ketones
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
DMAc
MeOH
MeOH
MeOH
MeOH
e
59
32
f
0.5
0.5
18
dg
,
78
a
Reaction conditions: 2a (0.250 mmol), 1a (0.375 mmol), base (x
b
c
equiv), solvent (1.0 mL), 110 °C, 10 h, air. GC yields. 0.1 equiv of
d
e
f
CuI was added. Isolated yield. 80 °C. Under N2 atmosphere.
g
Reaction conditions: 2a (5.0 mmol), 1a (7.5 mmol), Cs2CO3 (0.5
equiv), MeOH (5.0 mL), 110 °C, 24 h, air.
(entry 17). Meanwhile, we scaled up the model reaction to 5
mmol to show the possibility for large-scale operation (entry
18), and a satisfactory yield (78%) was obtained by prolonging
the reaction time to 24 h.
With the optimized conditions in hand, a series α,β-
unsaturated ketones were applied in the reaction to established
the scope and generality of this protocol (Scheme 2).
Chalcones containing electron-donating or electron-withdraw-
ing groups could react with 1a to give the corresponding 1,4-
a
Reaction conditions: cyclic ketone (0.250 mmol), 1 (0.375 mmol),
b
DMSO (1.0 mL), 110 °C, 24 h, air. Isolated yields are shown.
c
Reaction conditions: cycloheptanone (0.250 mmol), 1a (0.375
mmol), Cs2CO3 (0.125 mmol), MeOH (1.0 mL), 110 °C, 10 h, air.
d
e
2-Aminoethane-1-thiol was used. Reaction conditions: 5,5-dimethyl-
cyclohexane-1,3-dione (0.250 mmol), 1a (0.375 mmol), DBU (0.500
mmol), DMSO (1.0 mL), 110 °C, 10 h, air.
generate the 1,4-benzothiazine ring in lower yield (4g).
Moreover, cycloheptanone and cyclohexanedione could also
undergo this reaction with a change in the base and solvent (4f,
4h). To our delight, linear ketones could also react with 1 to
form 1,4-benzothiazine derivatives 5a−c in moderate to good
yields (Scheme 4). However, aliphatic ketones (e.g., pentan-3-
one and butan-2-one) failed to give the corresponding products
in the protocol.
Scheme 2. Reaction of o-Aminobenzenethiols with α,β-
Unsaturated Ketones
a b
,
The incorporation of fluoroalkyl substituents into hetero-
cyclic compounds has attracted specific interest because of their
ability to enhance the metabolic stability and membrane
permeability of the parent molecules.11 In addition, fluoroalkyl
Scheme 4. Reaction of o-Aminobenzenethiols with Linear
Ketones
a
Reaction conditions: 2 (0.250 mmol), 1 (0.375 mmol), Cs2CO3
b
(0.125 mmol), MeOH (1.0 mL), 110 °C, 10 h, air. Isolated yields are
shown. The configuration of 3g was uncertain. 2-Aminoethane-1-
thiol was used. 4,4-Dimethylcyclohex-2-en-1-one was used.
c
d
e
B
DOI: 10.1021/acs.orglett.6b03324
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Organic Letters
Letter
as a strong electron-withdrawing group significantly increases
the electrophilicity of the carbonyl group in ketones. Thus, we
treated fluoroalkyl ketones with o-aminobenzenethiols under
basic conditions, and the fluoroalkyl 1,4-benzothiazines were
obtained fortunately. In all cases, only tetrahedral adducts were
produced in moderate to good yields (6a−e; Scheme 5).12
Table 2. Control Experiments
Scheme 5. Reaction of o-Aminobenzenethiols with
ab
,
Fluoroalkyl Ketones
a
Reaction conditions: fluoroalkyl ketone (0.375 mmol), 1 (0.250
b
mmol), DBU (0.500 mmol), DMAc (1.0 mL), rt, 24 h, air. Isolated
yields are shown.
To further demonstrate the potential of the chemistry,
azaphenothiazine 7, whose derivatives have antiproliferative
activity toward cancer cells,13 was synthesized under identical
conditions (Scheme 6). Likewise, compound 8 derived from 2-
a
Scheme 6. Synthesis of Potential Drug Intermediates 7 and 8
Condition A: chalcone (0.250 mmol), 1a or 9 (0.375 mmol),
Cs2CO3 (0.125 mmol), MeOH (1.0 mL), 110 °C, 10 h, air. Condition
B: cyclohexene (0.250 mmol), 1a or 9 (0.375 mmol), DMSO (1.0
mL), 110 °C, 24 h, air. Condition C: propiophenone (0.250 mmol),
1a or 9 (0.375 mmol), Cs2CO3 (0.125 mmol), DMAc (1.0 mL), 110
°C, 10 h, air. Condition D: 1,1,1-trifluoropropan-2-one (0.375 mmol),
1a or 9 (0.250 mmol), DBU (0.500 mmol), DMAc (1.0 mL), rt, 24 h,
b
c
air. GC yields of 1,4-benzothiazines. 3.0 equiv TEMPO was used.
d
e
Acetophenone was used instead of propiophenone. Isolated yields.
50 °C. 110 °C. 3 equiv of 1a was used.
f
g
h
these results, it can be concluded that (1) the condensations
between ketones and amines are difficult in these systems; (2)
the initial step may be addition of the thiyl radical to the
ketone; (3) the condensation products cannot afford 1,4-
benzothiazines under identical conditions;15 (4) the intra-
molecular condensation is easier than the intermolecular
condensation (entry 8 vs 10).8,16
Although the detailed mechanism of this reaction remains to
be elucidated, a tentative pathway for the cyclization of ketones
and 2-aminobenzenethiols is proposed in Scheme 7. Initially,
thiyl radical 13 generated in situ from the 2-aminobenzenethiol
upon heating under an air atmosphere adds to the enol formed
by isomerization of the ketone to afford carbon radical
intermediate 14, after which a single electron transfer process
produces 15. Intermediate 15 can be transformed into the final
product by an intramolecular condensation route. If the
condensation product 16 is generated in some cases, it can
be further condensed to provide the 2-substituted benzothia-
zole byproduct.15 The base plays a dual role in the reaction: (1)
enhancing the nucleophilicity of enol and (2) promoting the
intramolecular condensation process.
amino-4-chlorobenzenethiol and ethyl 4,4,4-trifluoro-3-oxobu-
tanoate (Scheme 6) could be transformed into the correspond-
ing 4H-1,4-benzothiazine and sulfone, which are possible
antibacterial and antifungal agents, through dehydration and
oxidation routes, respectively.14
Further control experiments were performed to probe the
mechanism (Table 2). All four reactions were inhibited in the
presence of TEMPO, and the radical trapping products were
observed in these reactions by GC−MS (entries 1−4). These
results suggest that the transformation may include a radical
process. Only the undesired ring-opening product 5d could be
detected in the case of cyclopropyl(phenyl)methanone as a
radical clock experiment, further confirming the existence of a
radical intermediate (entry 12).7g
In order to find out the prior reaction center during the
cyclization reaction, 9 was reacted with five ketones under
optimized conditions (entries 5−9). Only acetophenone led to
a 15% yield of the condensation product. Compound 10 may
be the intermediate during the reaction since it can be
transformed into the desired product 5a even at lower
temperature (entry 10). Compound 11 failed to yield 5a, and
12 was obtained as a byproduct (entry 11). On the basis of
In summary, we have developed an efficient approach for the
generation of various 1,4-benzothiazine rings from 2-amino-
benzenethiols and ketones under transition-metal-free con-
C
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Scheme 7. Tentative Pathway for the Reaction of 2-
Aminobenzenethiols with Ketones
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1,4-benzothiazine derivatives, opening a new window of
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b03324.
(9) (a) Basta-Kaim, A.; Budziszewska, B.; Jaworska-Feil, L.; Tetich,
M.; Kubera, M.; Leskiewicz, M.; Otczyk, M.; Lason, W. Neuro-
psychopharmacology 2006, 31, 853. (b) Bate, A. B.; Kalin, J. H.;
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Experimental details and copies of NMR spectra of all
products (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: glu@njust.edu.cn.
*E-mail: yiwb@njust.edu.cn.
Notes
The authors declare no competing financial interest.
(10) Field, L. D.; Li, H. L.; Dalgarno, S. J.; McIntosh, R. D. Inorg.
Chem. 2013, 52, 1570.
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ACKNOWLEDGMENTS
■
We gratefully acknowledge the Natural Science Foundations of
China (21402093, 21476116) and Jiangsu Province
(BK20140776, BK20141394), the Chinese Postdoctoral
Science Foundation (2016T90465, 2015M571761), and the
Priority Academic Program Development of Jiangsu Higher
Education Institutions for financial support.
Sander, U.; Stahl, M. ChemBioChem 2004, 5, 637. (c) Muller, K.; Faeh,
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C.; Diederich, F. Science 2007, 317, 1881. (d) Purser, S.; Moore, P. R.;
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E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J.
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