Synthesis of Isothiochroman-3-ones via Metal-Free Oxidative Cyclization of Alkynyl Thioethers

Article abstract of DOI:10.1021/acs.orglett.8b03462

A novel Br?nsted acid-catalyzed oxidative C-H functionalization of alkynyl thioethers has been developed. This method allows the practical synthesis of valuable isothiochroman-3-ones in mostly moderate to good yields under mild reaction conditions and features a broad substrate scope and wide functional group tolerance. Moreover, this metal-free oxidation can also be used to promote formal N-H insertion involving an unexpected 1,2-sulfur migration, affording useful 1,4-benzothiazin-3-ones.

Full text of DOI:10.1021/acs.orglett.8b03462

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Synthesis of Isothiochroman-3-ones via Metal-Free Oxidative
Cyclization of Alkynyl Thioethers
Ying-Qi Zhang,†,§ Xin-Qi Zhu,†,§ Yang-Bo Chen,† Tong-De Tan,† Ming-Yang Yang,†
and Long-Wu Ye*,†,‡
†iChEM, State Key Laboratory of Physical Chemistry of Solid Surfaces and Key Laboratory for Chemical Biology of Fujian Province,
College of Chemistry and Chemical Engineering, Xiamen University, Xiamen 361005, China
‡State Key Laboratory of Organometallic Chemistry, Chinese Academy of Sciences, Shanghai 200032, China
S
* Supporting Information
ABSTRACT: A novel Brønsted acid-catalyzed oxidative C−H
functionalization of alkynyl thioethers has been developed.
This method allows the practical synthesis of valuable
isothiochroman-3-ones in mostly moderate to good yields
under mild reaction conditions and features a broad substrate
scope and wide functional group tolerance. Moreover, this
metal-free oxidation can also be used to promote formal N−H
insertion involving an unexpected 1,2-sulfur migration, affording useful 1,4-benzothiazin-3-ones.
Scheme 1. Metal-Free Oxidative C−H Functionalization of
Alkynes Using Pyridine N-Oxide as the External Oxidant
sothiochroman-3-ones are widely distributed sulfur hetero-
Icycles that are found in a variety of bioactive molecules, as
exemplified by their use as an aminopeptidase inhibitor,
agrochemical fungicide, and herbicide (Figure 1).1 It is
surprising, however, that only a few preparative methods have
been reported; they generally suffer from multistep synthesis,
limited substrate scope, inaccessible precursors, and low
efficiency.1,2 Therefore, the development of novel methods
for the preparation of isothiochroman-3-one scaffolds is still
highly desirable, especially those with high efficiency and
flexibility.
Figure 1. Isothiochroman-3-ones in bioactive molecules.
H functionalization of alkynyl aryl ethers, allowing the facile
synthesis of various benzofuranones (Scheme 1b).8b It is
notable that both cyclizations rely on the use of terminal
alkynes as substrates. In addition, such a metal-free alkyne
oxidation was also nicely exploited in the intermolecular
alkyne oxyarylations reported by Maulide and Shin.9
In the past decade, gold-catalyzed intermolecular N-oxide
oxidation of alkynes, mostly through an α-oxo gold carbene
pathway, has attracted considerable attention, and an
incredible variety of efficient synthetic methods based on
this approach have been developed.3,4 It is worth noting that
later studies revealed that other transition metals such as
rhodium, palladium, and zinc could also catalyze this type of
alkyne oxidation.5−7 Despite these achievements, successful
examples of metal-free alkyne oxidations are rare. In 2012,
Gong and co-workers reported an elegant protocol for the
MsOH-mediated oxidative C−H functionalization of aryl
alkynes, which was the first metal-free alkyne oxidation by N-
oxides (Scheme 1a).8a One year later, Hashmi and co-
workers also disclosed a related HBF4-catalyzed oxidative C−
In our recent study of ynamide chemistry,10,11 we have
developed a diverse array of ynamide-oxidation-initiated
tandem reactions, leading to the efficient synthesis of
structurally complex N-containing molecules.7,12 However,
compared with the ynamide chemistry, the chemistry of
thioynol ethers has been far less exploited.13 To the best of
Received: October 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b03462
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
our knowledge, N-oxide oxidation of alkynyl thioethers has
not been reported to date. In this communication, we
describe a Brønsted acid-catalyzed oxidative C−H function-
alization of alkynyl thioethers (Scheme 1c). This method
allows the practical synthesis of valuable isothiochroman-3-
ones in mostly moderate to good yields under mild reaction
conditions and features a broad substrate scope and wide
functional group tolerance. Moreover, this metal-free
oxidative cyclization14 can also be used to promote facile
formal N−H insertion involving an unexpected 1,2-sulfur
migration, leading to useful 1,4-benzothiazin-3-ones.
Scheme 2. Brønsted Acid-Catalyzed Oxidative Cyclization
of Internal Alkynyl Thioethers
a
At the outset, internal alkynyl thioether 1a, which was
readily prepared from the corresponding terminal alkyne, was
used as the model substrate, and some of the results are
outlined in Table 1. As expected, typical gold catalysts such
a
Table 1. Optimization of the Reaction Conditions
a
Reactions were run in vials with [1] = 0.05 M. Isolated yields are
b
reported. 6 mmol scale using 10 mol % HNTf2 and [1a] = 0.2 M for
6 h.
functionalization, affording the desired isothiochroman-3-ones
2 in mostly high yields (42−86%). Alkynyl thioethers bearing
electron-withdrawing substituents such as F, Cl, Br, and even
CN and CO2Me on the aromatic ring (R2 = Ar) were
compatible with this oxidative cyclization, producing the
corresponding products 2a−g in generally good to excellent
yields (entries 1−7). In addition, alkynyl thioethers with
electron-donating substituents such as Me and MeO were
also suitable substrates, delivering the desired products 2h−j
in 53−74% yield (entries 8−10). This cascade cyclization was
also extended to the naphthyl-substituted thioynol ether, and
the desired product 2k was formed in 61% yield (entry 11;
the structure of 2k was confirmed by X-ray diffraction). In
the case of the substrate bearing an electron-donating
methoxy substituent at the meta position, 3:1 regioselectivity
and a 66% combined yield of 2l and 2l′ was obtained (entry
12). Attempts to extend the reaction to electron-deficient aryl
substrates failed (entries 13 and 14), and similar decreased
efficiency was also observed in Hashmi’s method8b and other
protocols for oxidative cyclization.16 Finally, a gram-scale
synthesis was also feasible (entry 1), highlighting the
synthetic utility of this chemistry.
Moreover, this metal-free oxidative cyclization could also
be applied to terminal alkynyl thioethers. As depicted in
Scheme 3, the tandem reaction occurred efficiently with
various alkynyl thioethers bearing electron-donating groups,
leading to the corresponding isothiochroman-3-ones 2o−t in
32−84% yield (entries 1−6). In addition, disubstituted and
sterically hindered thioynol ethers were also suitable
substrates and were converted into the desired products 2u
(81%) and 2v (84%), respectively (entries 7 and 8). Notably,
a
Reaction conditions: [1a] = 0.05 M. DCE: 1,2-dichloroethane.
b
Estimated by 1H NMR analysis using diethyl phthalate as an internal
c
reference. >95% of 1a remained unreacted.
as Ph3PAuNTf2 and IPrAuNTf2 were not effective in
catalyzing this reaction (entries 1 and 2). We then screened
different non-noble metals (entries 3−6) and were delighted
to find that Sc(OTf)3 could catalyze the oxidative cyclization
to deliver the desired isothiochroman-3-one 2a in 69% yield
(entry 5). Pleasingly, further screening of Brønsted acid
catalysts (entries 7−11) revealed that a 90% yield was
achieved by employing HNTf2 as the catalyst (entry 11).15
The use of other solvents such as PhCl and toluene (entries
12 and 13) and other oxidants (see the Supporting
Information for details) failed to improve the reaction.
Here it should be mentioned that the low efficiency with less
bulky oxidants is largely attributed to the fact that the
pyridine eventually released from the corresponding less
bulky pyridine N-oxide may poison the acid catalyst.
With the optimal reaction conditions in hand (Table 1,
entry 11), the scope of this metal-free oxidative cyclization of
internal alkynyl thioethers was first examined (Scheme 2). All
of the alkynyl thioethers 1 underwent smooth oxidative C−H
B
DOI: 10.1021/acs.orglett.8b03462
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Letter
Scheme 3. Brønsted Acid-Catalyzed Oxidative Cyclization
a
of Terminal Alkynyl Thioethers
Scheme 4. Plausible Reaction Mechanism
a
Reactions were run in vials with [1] = 0.05 M. Isolated yields are
reported.
the reaction even proceeded smoothly with an alkynyl
thioether bearing an alkenyl group to produce the desired
product 2w in 57% yield (entry 9). Finally, it was found that
thioynol ethers containing different R2 groups were
competent substrates, delivering the corresponding products
2x−z in 51−90% yield (entries 10−12). Thus, this metal-free
protocol provides an efficient and practical route for the
preparation of the synthetically useful isothiochroman-3-one
scaffold.
The possibility of extending this reaction to the synthesis
of seven-membered rings was also examined. Under the
above optimized reaction conditions, the oxidative cyclization
of thioynol ether 3a led to the formation of the anticipated
benzothiepin-2-one 4a in 57% yield (eq 1).
Subsequent deprotonation−aromatization leads to the target
product 2a and regenerates the proton catalyst.
In summary, we have developed a practical and general
method for the construction of a variety of valuable
isothiochroman-3-ones through metal-free oxidative cycliza-
tion of alkynyl thioethers. Importantly, this protocol
represents the first N-oxide oxidation of alkynyl thioethers.
This method features a broad substrate scope that is
applicable to both terminal and internal alkynyl thioethers
and has a wide functional group tolerance. Moreover, this
metal-free oxidative cyclization can also be used to promote
facile formal N−H insertion involving an unexpected 1,2-
sulfur migration, leading to useful 1,4-benzothiazin-3-ones.
We then wondered whether this metal-free cyclization
could be applied to the oxidative formal N−H insertion. As
shown in eqs 2 and 3, the oxidative cyclization of terminal
and internal alkynyl thioethers 5 proceeded smoothly under
the optimal reaction conditions, affording the unexpected
benzothiazin-3-ones 6a−c in respectable yields (the structure
of 6a was confirmed by X-ray diffraction).17 The reaction
presumably involves a key 1,2-sulfur migration,18 which has
very recently been disclosed by our group in the relevant
amination-initiated tandem reaction.19
On the basis of the above experimental observations and
our previous work on ynamide oxidation,7,12 a plausible
mechanism to rationalize the formation of 2a is proposed
(Scheme 4). Initially, 2,6-dibromopyridine N-oxide attacks
the Brønsted acid-activated thioynol ether 1a to produce
vinyl sulfide intermediate B, which reacts via an intra-
molecular SN2′ pathway4f,l to generate intermediate C.
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.8b03462.
Experimental procedures and spectral data for all new
compounds (PDF)
Accession Codes
CCDC 1873437 and 1873438 contain the supplementary
crystallographic data for this paper. These data can be
C
DOI: 10.1021/acs.orglett.8b03462
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Organic Letters
Letter
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obtained free of charge via www.ccdc.cam.ac.uk/data_-
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AUTHOR INFORMATION
■
Corresponding Author
*E-mail: longwuye@xmu.edu.cn.
ORCID
Long-Wu Ye: 0000-0003-3108-2611
Author Contributions
§Y.-Q.Z. and X.-Q.Z. contributed equally.
(8) (a) Chen, D.-F.; Han, Z.-Y.; He, Y.-P.; Yu, J.; Gong, L.-Z.
Notes
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̈
Rudolph, M.; Rominger, F.; Hashmi, A. S. K. Angew. Chem., Int. Ed.
2013, 52, 12727.
The authors declare no competing financial interest.
́
(9) (a) Chen, X.; Ruider, S. A.; Hartmann, R. W.; Gonzalez, L.;
ACKNOWLEDGMENTS
■
Maulide, N. Angew. Chem., Int. Ed. 2016, 55, 15424. (b) Patil, D. V.;
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Angew. Chem., Int. Ed. 2017, 56, 3670. For a relevant metal-free
reaction of electron-deficient alkynes, see: (c) Zhang, B.; Huang, L.;
Yin, S.; Li, X.; Xu, T.; Zhuang, B.; Wang, T.; Zhang, Z.; Hashmi, A.
S. K. Org. Lett. 2017, 19, 4327.
We are grateful for the financial support from the National
Natural Science Foundation of China (21572186, 21622204,
and 21772161), the President Research Funds from Xiamen
University (20720180036), PCSIRT, and NFFTBS
(J1310024).
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