Metal-free direct C(sp3)?H functionalization of 2-alkylthiobenzoic acid to access 1,3-benzooxathiin-4-one

Article abstract of DOI:10.1016/j.cclet.2020.11.036

Metal-free direct α-C(sp³)?H intramolecular cyclization of 2-alkylthiobenzoic acid in the presence of Selectfluor is described. This novel strategy provides a facile and efficient method to access important 1,3-benzooxathiin-4-one derivatives w

Full text of DOI:10.1016/j.cclet.2020.11.036

Chinese Chemical Letters 32 (2021) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Metal-free direct C(sp3)ÀH functionalization of 2-alkylthiobenzoic acid
to access 1,3-benzooxathiin-4-one
*
*
Ke Yang , Yi Li, Mengjie Song, Shengfei Dai, Zheng-Yi Li , Xiaoqiang Sun
Jiangsu Key Laboratory of Advanced Catalytic Materials & Technology, School of Petrochemical Engineering, Changzhou University, Changzhou, 213164, China
A R T I C L E I N F O
A B S T R A C T
Metal-free direct α-C(sp3)ÀH intramolecular cyclization of 2-alkylthiobenzoic acid in the presence of
Selectfluor is described. This novel strategy provides a facile and efficient method to access important 1,3-
benzooxathiin-4-one derivatives with good functional groups tolerance and yields.
© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Article history:
Received 25 September 2020
Received in revised form 9 November 2020
Accepted 11 November 2020
Available online 23 November 2020
Keywords:
Metal-free
C(sp3)ÀH functionalization
Selectfluor
1,3-Benzooxathiin-4-one
Organic synthesis
1,3-Benzooxathiin-4-ones have received much attention due to
their vital use in a large number of insecticidal and fungicidal
agents, crop protection agents, and food additives (Fig. 1) [1–3].
Previous methods for the synthesis of 1,3-benzooxathiin-4-ones
mainly rely on the cross-coupling of thiophenol derivatives with
alkynes [4–7] and alkenes [8,9], or the Pummerer reaction of
sulfoxide derivatives [10,11]. However, these methods always
suffer from some drawbacks, including the use of odour smelling
thiophenols, the requirement of pre-functionalization of thio-
ethers or limited substrate scope.
Recently, direct CÀH bond functionalization has been regarded
as one of the most effective and direct methods for the
construction of CÀC or CÀheteroatom bond [12–24]. Within this
reaction class, transition-metal mediated C(sp3)ÀH bond func-
tionalization of thioether derivatives has been developed to
synthesize 1,3-benzooxathiin-4-ones. The Porcel group reported
the allylic CÀH bond intramolecular cyclization of 2-(allylthio)
benzoic acid mediated by the excess amounts of AgOAc
(Scheme 1a) [25]. Moreover, our group also demonstrated the
Ag2O-promoted intramolecular C(sp3)ÀH bond functionalization
of 2-methylthiobenzamide and sequential acidolysis to access 4H-
benzo[d][1,3]oxathiin-4-one (Scheme 1b) [26]. However, the
current methods often need expensive silver salts and with the
limited substrate scope. Therefore, development of a metal-free
and highly efficient method via a direct C(sp3)ÀH functionalization
for the synthesis of 1,3-benzooxathiin-4-ones would be of great
significance.
Selectfluor, as a remarkable electrophilic fluorinating reagent,
has been widely used in the fluorination process in recent years
due to its low toxicity, high thermal stability, good solubility and
stability in polar solvents [27–30]. Besides, it can also be employed
as a radical initiator, fluorine cation initiator and transition metal
oxidant to achieve “fluorine-free” reactions [31–44]. In the
continuing efforts for developing novel metal-free strategies in
the direct C(sp3)ÀH functionalization, herein we disclose the
Selectfluor-mediated cyclization of 2-alkylthiobenzoic acid to
access 1,3-benzooxathiin-4-one via a direct sp3 α-CÀH function-
alization reaction (Scheme 1c).
Our investigation began with the direct C(sp3)ÀH intramolecu-
lar cyclization of 2-(ethylthio)benzoic acid 1a in the presence of
Selectfluor in DCE at 80 ꢀC, the desired product 2a was isolated in
53% yield (Table 1, entry 1). To our delight, the subsequent
examination of different reaction solvents indicated that MeCN
was the optimal solvent, affording the desired product 2a in 82%
isolated yield (Table 1, entries 2–7). Next, the additive agent
screening showed that none of the other additives provided better
results than Selectfluor (Table 1, entries 8–14). It was then noticed
that the yield of 2a could not be improved any more by increasing
or decreasing the amounts of Selectfluor and the reaction
temperature (Table 1, entries 15–18). Finally, the desired product
2a could not be detected in the absence of Selectfluor (Table 1,
entry 19).
With the optimized reaction conditions in hand, the substrate
scope study on the sulfur atom substituents of 2-alkylthiobenzoic
* Corresponding authors.
E-mail addresses: keyang@cczu.edu.cn (K. Yang), zyli@cczu.edu.cn (Z.-Y. Li).
https://doi.org/10.1016/j.cclet.2020.11.036
1001-8417/© 2020 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.

K. Yang, Y. Li, M. Song et al.
Chinese Chemical Letters 32 (2021) xxx–xxx
Table 1
Optimization of reaction conditions.a
Fig. 1. Selected important 1,3-benzooxathiin-4-one derivatives.
Entry
Additive (equiv.)
Solvent
Temp (oC)
Yield (%)b
1
2
3
4
5
6
7
8
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor-II (1.5)
NFSI (1.5)
NFPT (1.5)
K2S2O8 (1.5)
TBHP (1.5)
AIBN (1.5)
PhI(OAc)2 (1.5)
Selectfluor (1.5)
Selectfluor (1.5)
Selectfluor (1.0)
Selectfluor (2.0)
—
DCE
80
80
80
80
80
80
80
80
80
80
80
80
80
80
60
100
80
80
80
53
82
0
39
0
MeCN
MeOH
Acetone
1,4-Dioxane
THF
0
0
DMSO
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
56
54
66
10
28
0
67
75
70
63
27
0
9
10
11
12
13
14
15
16
17
18
19
Selectfluor = 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo-[2.2.2]octane bis(tetra-
fluoroborate), Selectfluor-II = 1-fluoro-4-methyl-1,4-diazoniabicyclo-[2.2.2]octane-
bis (tetrafluoroborate), NFSI
=
N-fluorobenzenesulfonimide, NFPT = 1-
fluoropyridinium triflate, TBHP = tert-butyl hydroperoxide, AIBN = azodiisobutyr-
Scheme 1. Direct C(sp3ÀH bond functionalization for the construction of 1,3-
onitrile.
a
Conditions: 1a (0.2 mmol), additive (0.2ꢁ0.4 mmol), solvent (2.0 mL), temper-
benzooxathiin-4-one derivatives.
ature, 12 h.
b
Isolated yield.
acid was carried out in Scheme 2. As expected, the substrates
bearing different linear and branched alkyl substituents on the
sulfur atom, including methyl, ethyl, n-propyl, n-butyl, n-hexyl, i-
propyl and i-butyl, were transformed to the desired products 2a-g
in good yields. Moreover, the substrates with a benzyl or phenethyl
group also gave the desired products 2h-i in excellent yield. In
addition, both cyano- and ester-substituted substrate were well-
tolerated to afford the desired products 2j and 2k in 81% and 63%
yield. It was noteworthy that the highly reactive allyl and propargyl
substrates could also provide the desired products 2l-m in good
yield.
isotope effect was observed and the cleavage of the C(sp3)ÀH bond
may not be involved in a rate-determining step (Scheme 4d).
On the basis of previous literatures [26,45–54] and our control
experiments,
a plausible mechanism has been depicted in
Scheme 5. The initial oxidation of 2-methylthiobenzoic acid 1b
by Selectfluor affords the radical A and radical cation B [45–48].
Then the carbon-centered radical C can be formed through a 1,6-H
Next, the substrate scope of substituents on the aromatic ring
was also tested (Scheme 3). Both electron withdrawing and
electron-donating groups on the phenyl ring were compatible
under the current reaction system, affording the desired products
2n-u in good yields. Notably, a variety of functional groups such as
methyl, methoxy and halogen groups were well-suited for this
reaction, allowing for further transformations of the initial
products. However, the pyridine-containing substrate 1v failed
to access the desired product 2v.
To provide some insights into the reaction mechanism, a series
of control experiments were carried out (Scheme 4). Firstly, radical
trapping experiments were performed, and the results showed
that the addition of TEMPO inhibited this process, suggesting that a
single electron transfer (SET) may be involved in the reaction
(Scheme 4a). Furthermore, the reaction of sulfoxide 3 with
Selectfluor failed to produce the desired product 2b, indicating
that the sulfoxide intermediate may not be involved in this
reaction (Scheme 4b). Next, the H/D exchange could not be
detected when this reaction was performed with an isotopically
labelled substrate [D]-1b (Scheme 4c). The KIE experiment
between 1b and [D]-1b showed that the second-order of kinetic
Scheme 2. Substrate scope of substituents on the sulfur atom. Reaction conditions:
1 (0.2 mmol), Selectfluor (0.3 mmol), MeCN (2.0 mL), 80 ꢀC, 12 h. Isolated yield.
2

K. Yang, Y. Li, M. Song et al.
Chinese Chemical Letters 32 (2021) xxx–xxx
Scheme 5. The proposed mechanism.
Scheme 3. Substrate scope of substituents on the aromatic ring. Reaction
conditions:
Isolated yield.
1
(0.2 mmol), Selectfluor (0.3 mmol), MeCN (2.0 mL), 80 ꢀC, 12 h.
radical shift process [49,50]. Subsequently, the radical C is oxidized
to the corresponding carbocation D and its isomer E in the
presence of radical cation B and Selectfluor [51,52]. Finally, an
intramolecular cyclization of intermediate E and the sequential
Scheme 6. A gram-scale reaction for the synthesis of benzooxathiin-4-one 2b.
deprotonation provide the desired product 2b. However,
a
(30 mL) at 80 ꢀC, the desired product 2b was obtained in 78%
isolated yield.
plausible pathway involving α-C–H fluorination and sequential
intramolecular cyclization cannot be excluded at the present stage
[53,46–54].
In order to illustrate the synthetic utility of this novel method, a
gram-scale reaction for the synthesis of benzooxathiin-4-one 2b
was carried out (Scheme 6). When 2-(methylthio)benzoic acid 1b
(1.68 g,10 mmol) was treated with 1.5 equiv. of Selectfluor in MeCN
In summary, an efficient and direct cyclization of 2-alkylth-
iobenzoic acid via a Selectfluor-promoted α-C(sp3)ÀH functional-
ization has been developed. This process may involve a radical
pathway in the presence of Selectfluor. Moreover, this metal-free
strategy also provides an important complementary method to
access various 1,3-benzooxathiin-4-one derivatives.
Declaration of competing interest
The authors report no declarations of interest.
Acknowledgments
We gratefully acknowledge the financial support from the
National Natural Science Foundation of China (Nos. 21572026,
21702019), Advanced Catalysis and Green Manufacturing Collabo-
rative Innovation Center, Changzhou University.
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