Intramolecular dehydrogenative C-S bond coupling of thioamides to form 1,3-benzothiazines under metal-free conditions

Article abstract of DOI:10.1039/c9ob00237e

A novel HTIB-promoted direct intramolecular dehydrogenative C-S bond coupling reaction of thioamides has been developed to provide 1,3-benzothiazine derivatives in good yields. The reaction proceeds smoothly to reach completion at room temperature within 1 min under metal-free conditions. This protocol provides a mild and efficient strategy for the synthesis of six-membered N,S-containing heterocycles. Preliminary mechanistic studies indicate that a spirocyclic intermediate might be involved.

Full text of DOI:10.1039/c9ob00237e

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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Intramolecular Dehydrogenative C–S Coupling of Thioamides to
Form 1,3‐Benzothiazines under Metal‐Free Conditions
Received 00th January 20xx,
Accepted 00th January 20xx
Li‐Rong Wen, Cheng‐Cheng Zhou, Ming‐Zhe Zhu, Shu‐Guang Xie, Wei‐Si Guo* and Ming Li*
DOI: 10.1039/x0xx00000x
A novel HTIB‐promoted direct intramolecular dehydrogenative C–S bond coupling reaction of thioamides has been
developed to provide 1,3‐benzothiazine derivatives in good yields. The reaction proceeds smoothly at room temperature
within 1 min under metal‐free conditions. This protocol provides a mild and efficient strategy for the synthesis of six‐
membered N,S‐containing heterocycles. Preliminary mechanistic studies indicate that a spirocyclic intermediate might be
involved.
Introduction
Benzothiazine scaffold as
a
privileged structure in
pharmaceuticals exhibits versatile activities,1 such as anti‐HIV,2
antimycobacterial,3 anti‐inflammatory,4 and antitumor activities.5
The representative BTZ043 is a candidate for therapy of drug‐
sensitive and drug‐resistant tuberculosis.6 BTZO‐1,7 a promising
cardioprotective agent, also contains the benzothiazine motif
(Figure 1). Therefore, the synthesis of benzothiazines has been an
on‐going attractive research field. Most of the reported approaches
rely on either intramolecular SNAr processes8 or metal‐catalyzed C–
S bond coupling reactions,9 both using substituted haloarenes as
reactants. In 2017, Peñéñory et al.10 established a CuI‐catalyzed
one‐pot process for the synthesis of 1,3‐benzothiazines from 1‐
(azidomethyl)‐2‐iodobenzene (Scheme 1, eq 1). Very recently, a
new method for the preparation of 1,3‐benzothiazines has been
developed using isocyanides and sulfoxides (Scheme 1, eq 2).11
Despite the advanced progress in the area, these methods usually
accompanied by harsh reaction conditions, low functional group
tolerance, and waste production. Thus, a facile and mild approach
for the synthesis of 1,3‐benzothiazines is highly desired.
Scheme 1 Strategies for the synthesis of 1,3‐benzothiazines.
Hypervalent iodine(III) reagents12 have gained much
attention due to their low toxicity, high reactivity, and mild
reaction conditions. Iodobenzene diacetate (PIDA) and
phenyliodine bis(trifluoroacetate) (PIFA) are the representative
examples, which were often used in intramolecular oxidative
coupling reactions to form carbon‐heteroatom bonds,13 whereas
the reactions promoted by Koser’s reagent (HTIB) were rarely
reported.14 Thioamides,15 as versatile synthons in organic
synthesis, are widely applied in the construction of five‐
membered heterocycles, such as thiazoles,16 thiazolines,17 and
thiazolinones.18 However, to the best of our knowledge, the
construction of six‐membered 1,3‐benzothiazines via direct
dehydrogenative C–S bond coupling of thioamides has never
been reported. Based on our previous study on N,S‐containing
heterocycles,19 we report herein a fast and efficient method for
the synthesis of 1,3‐benzothiazine derivatives through a direct
intramolecular dehydrogenative C–S coupling reaction
(Scheme 1, eq 3). Interestingly, a substituent effect that
enabled ipso‐cyclization and migration was also observed.
Figure 1 Biologically active benzothiazine derivatives.
State Key Laboratory Base of Eco‐Chemical Engineering, College of Chemistry and
Molecular Engineering, Qingdao University of Science and Technology, Qingdao
266042, P. R. China. E‐mail: wsguo@qust.edu.cn, liming928@qust.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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DOI: 10.1039/C9OB00237E
ARTICLE
Journal Name
well, and products 3f‐j were obtained in moderate yields. Two
unseparated isomers 3k/3k’ or 3l/3n were generated in high yield in
a ratio of 4.4:1 or 3.2:1 when m‐methyl substrate or m‐methoxy
substrate was used, respectively. o‐Methyl substrate 1m produced
benzothiazines 3m/3k’ in a 1:10 ratio with 87% overall yield, while
only migration product 3n was obtained in 61% yield when o‐
methoxy substrate was used. The corresponding benzothiazines
were not obtained when halide substituents including 4‐chloro and
4‐bromo substrates were used. Subsequently, the scope of
phosphine oxides was evaluated. Thioamides 1o‐r with different
phosphoryl groups such as methyl, methoxy, and halogen groups
were all proceeded smoothly, benzothiazines 3o‐r were formed in
moderate to high yields. Additionally, the tricyclic products 3s and
3t were isolated in 92% and 94% yields, respectively. Thioamide 1u
bearing a thiophene group was also tolerated to provided product
3u in 85% yield.
Results and discussion
Diphenylphosphoryl thioamide 1a and hydroxyl(phenyl)
iodotosylate (HTIB) 2a was used as the model substrates to examine
the reaction conditions. 1,3‐Benzothiazine 3a was generated in 85%
yield utilizing hexafluoroisopropanol (HFIP) as the solvent at room
temperature for 1 min (Table 1, entry 1). Other hypervalent iodine
reagents, such as PIDA, PIFA, p‐F‐HTIB 2b, and p‐Me‐HTIB 2c, were
all suitable for the reaction, but gave relatively lower yields (Table 1,
entries 2‐5). Solvent screening results revealed that HFIP was the
best choice (Table 1, entries 6‐9). Similar yields were obtained by
increasing the amount of HTIB to 1.2 equiv. or performing the
reaction under nitrogen atmosphere (Table 1, entries 10 and 11).
a
Table 1 Optimization of the reaction conditions
R3
R3
S
OTs
I
N
HFIP, rt
N
H
R2
R1
OH
R1
R2
air, 1 min
S
3
1
2a
MeO
MeO
O
O
N
N
N
N
O
O
O
O
P
Me
P
S
S
P
P
S
S
Ph
Ph
Ph
3a, 85%
Ph
3b, 83%
Ph
Ph
Ph
Ph
3c, 45%
3d, 78%
Entry
Hypervalent iodine(III)
reagents (equiv)
Solvent
Yieldb (%)
Ph
N
N
N
O
O
O
N
S
P
S
P
S
P
S
O
P
1
2a (1.0)
PIDA (1.0)
PIFA (1.0)
2b (1.0)
2c (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.0)
2a (1.2)
2a (1.0)
HFIP
HFIP
HFIP
HFIP
HFIP
DCM
Toluene
MeOH
TFE
85
Ph
Ph
Ph
Ph
Ph
Ph
3g, 62%
3e, 80%
Ph
3f, 64%
Ph
3h, 70%
2
63
p-ClC6H4
p-FC6H4
N
N
3
67
N
O
N
O
O
O
P
S
P
S
P
P
S
S
Ph
O
Ph
Ph
4
78
Ph
Ph
Ph
Ph
3i, 52%
Ph
3j, 40%
3k/3k', 93%, ratio 4.4: 1
5
81
MeO
N
N
N
N
O
O
O
6
trace
trace
25
P
S
P
S
P
S
P
S
Ph
Ph
Ph
Ph
Ph
OMe
Ph
Ph
Ph
7
3l/3n, 83%, ratio 3.2: 1
3m/3k', 87%, ratio 1: 10
N
O
P
N
N
N
8
O
P
O
O
P
p-MeOC6H4
3p, 92%
Br
S
P
S
S
S
p-ClC6H4
p-MeC6H4
p-OMeC6H4
Ph
p-ClC6H4
Ph
9
51
p-MeC6H4
3o, 86%
OMe
3q, 80%
3n, 61%
10
11c
HFIP
HFIP
79
N
S
N
O
O
N
O
N
O
85
S
S
P
P
p-FC6H4
Ph
S
P
Ph
p-FC6H4
S
P
Ph
a Reaction conditions: 1a (0.4 mmol), 2a (0.4 mmol), HFIP (4.0 mL), rt, air, 1 min.
b Isolated yield. c N2 atmosphere
Ph
Ph
Ph
3u, 85%
3r, 61%
3s, 92%
3t, 94%
MeO
MeO
N
N
N
N
S
Ph
S
CF3
S
CF3
S
CF3
With the optimum conditions in hand, the substrate scope was
explored (Scheme 2). Substituents on the phenyl ring of thioamides
1 were first examined. Product 3b with 4‐methyl group was formed
as a single isomer in 83% yield. The reactions proceeded smoothly
with di‐substituted substrates, 3,4‐dimethoxy product 3c and 3,4‐
methylenedioxy product 3d were afforded in 45% and 78% yields,
respectively. Notably, when β‐naphthalenyl thioamide 1e was
chosen as a substrate, product 3e was isolated as a single isomer in
80% yield. Branched substrates were also tolerated, reactions of
various R3 substituents such as alkyl, aryl, and cyclohexyl all worked
3v, 81%
3w, 75%
3x, 77%
3y, 82%
N
N
S
N
S
N
S
S
CI
OMe
OMe
CF3
OMe
3z, 68%
3aa, 73%
3ac, 75%
3ab, 64%
N
S
N
S
3ae, N.P.
3ad, N.P.
Scheme 2 Substrate scope. The reactions were performed with 1
(0.4 mmol) under the standard conditions.
2 | J. Name., 2012, 00, 1‐3
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ARTICLE
phosphoryl
groups,
substrates
with
3b). Furthermore, compound 3a can be easily converted to 1,3‐
benzothiazin‐4‐one 4a through KMnO4 oxidation (Scheme 3c).
The reaction was not obviously inhibited by the typical
trifluoromethyl group were compatible, the desired 1,3‐
benzothiazines 3v‐3x were obtained in good yields (Scheme 2).
Furthermore, the scope of aryl substituents was also examined. The
reactions of thioamides bearing electron‐donating or withdrawing
groups on the phenyl ring all proceeded well, generating products
3y‐3ac in moderate to good yields. Unfortunately, products with
cyclohexyl group 3ad and n‐propyl group 3ae were not obtained
due to rapid decomposition.
radical
scavengers
2,2,6,6‐tetramethylpiperidine‐1‐oxyl
(TEMPO) or 1,1‐diphenylethylene (DPE), indicating that the
radical pathway might not be involved in the reaction (Scheme
3d). Considering the literature reports20 and the above
experimental results, a reasonable mechanism was proposed
in Scheme 4. Initially, HTIB activates sulfur atom of thioamides
1
to form intermediate
stabilized by HFIP, which exhibits strong ionizing ability.21 The
desired product is produced through intramolecular
A. The intermediate A could be
3
cyclization (path a). However, we cannot exclude another
possible pathway through S‐migration of spirocyclic
intermediate
C (path b). Based on our experiment results, the
position of substituents R1 has obvious effect on the
construction of products. When o‐methyl substrate 1m was
used, intermediate C1 can undergo C‐migration to generate
3k’ as a major product (path c). Interestingly, for m‐methyl
substrate 1k, compound 3k’ was also formed as a minor
isomer through S‐migration of intermediate C2 (path d).
Conclusions
In conclusion, we have developed a practical intramolecular
dehydrogenative C–S coupling reaction of thioamides using
readily available HTIB as the oxidant. This protocol provides a
mild and efficient approach for the synthesis of 1,3‐
benzothiazine derivatives under metal‐free conditions, which
tolerates various functional groups. All the reactions were
completed within 1 min at room temperature. Preliminary
studies indicate that different pathways are involved in the
mechanism. Further discovery is currently in progress for the
hypervalent iodine‐mediated oxidative coupling reactions.
Scheme 3 One‐pot, scaled‐up, and control experiments.
Conflicts of interest
There are no conflicts to declare.
Acknowledgements
This work was financially supported by the National Natural
Science Foundation of China (21572110), the Key Research and
Development Project of Shandong Province (2017GHY15125),
and the Applied Basic Research Project (Youth Special) of
Qingdao (16‐5‐1‐98‐jch).
Scheme 4 Plausible mechanism.
Notes and references
To demonstrate the utility of this protocol, a one‐pot process was
performed from isothiocyanate as starting material, the reaction
worked smoothly to provide 3a in 60% yield (Scheme 3a). In
addition, a gram‐scale reaction using 6 mmol 1a was performed
under the standard conditions, producing 3a in 75% yield (Scheme
1
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Table of contents
Intramolecular Dehydrogenative C–S Coupling of
Thioamides to Form 1,3-Benzothiazines under Metal-Free
Conditions
Li-Rong Wen, Cheng-Cheng Zhou, Ming-Zhe Zhu, Shu-Guang Xie, Wei-Si Guo* and Ming Li*
R3
R3
S
HTIB
N
R1
N
R2
R1
H
HFIP, rt, 1 min
S
R2
R2 = PO(Ar)2, Ar, CF3
28 examples
mild conditions
easy operation
fast reaction
broad substrate scope
A new protocol for the construction of 1,3-benzothiazines was developed through direct
intramolecular dehydrogenative C–S bond coupling.