Copper-Catalyzed Trifluoromethylation/Cyclization of Alkynes for Synthesis of Dioxodibenzothiazepines

Article abstract of DOI:10.1021/acs.orglett.1c00344

A facile and efficient approach for the synthesis of the CF3-containing dioxodibenzothiazepines has been developed via copper-catalyzed trifluoromethylation/cyclization of alkynes utilizing a radical relay strategy. This method has demonstrated low cataly

Full text of DOI:10.1021/acs.orglett.1c00344

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Letter
Copper-Catalyzed Trifluoromethylation/Cyclization of Alkynes for
Synthesis of Dioxodibenzothiazepines
Zi-Qi Zhang, Yi-Hao Xu, Jing-Cheng Dai, Yan Li, Jie Sheng, and Xi-Sheng Wang*
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ABSTRACT: A facile and efficient approach for the synthesis of the CF3-containing dioxodibenzothiazepines has been developed
via copper-catalyzed trifluoromethylation/cyclization of alkynes utilizing a radical relay strategy. This method has demonstrated low
catalyst loading, high regiocontrol, and broad scope under mild conditions. Good compatibility for the N-protecting group, gram-
scale experiment, and further derivation of product prove the versatility of this transformation.
ulfonamides are undisputed relevant targets for drug
design due to their exhibited antithyroid, antibacterial,
Scheme 1. Approaches to 7-Membered Cyclic Sulfonamides
S
anti-inflammatory, anticancer, diuretic, antihypertensive, hypo-
glycemic, and anticonvulsant properties.1 As a special class of
7-membered cyclic sulfonamide, the dioxodibenzothiazepine
skeleton is one of the most important structures existing in
sulfonamide drug molecules such as the commercial
antidepressant drugs tianeptine and zepastine. What’s more,
other compounds bearing the 7-membered sulfonamide
moieties have also exhibited biological activity, such as
anticancer (farnesyltransferase inhibitor) (Figure 1).2 Com-
Figure 1. Selected biologically active compounds containing the
dioxodibenzothiazepine skeleton.
but it requires more than seven steps, which in turn reduces
the yield and the efficiency (Scheme 1b).2,3a
pared to the open-chain sulfonamides, efficient synthetic
methods to construct such 7-membered cyclic sulfonamides
are still limited.3 For example, palladium-catalyzed direct C−H
functionalization using aryl halides3g−k or an intramolecular
oxidative C−H coupling reaction of two C(sp2)−H bonds3h
has been developed as a practical approach to 7-membered
cyclic sulfonamides, but only cyclic sulfonamides embedded
with biaryls are applicable to these protocols (Scheme 1a). The
traditional methods to make 7-membered cyclic sulfonamides
are normally based on the Friedel−Crafts acylation strategy,
Usually, the radical cyclization reactions have the advantages
of high regioselectivity and efficiency.4 Particularly, as an
Received: January 29, 2021
Published: February 26, 2021
https://dx.doi.org/10.1021/acs.orglett.1c00344
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2194−2198
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a
excellent radical acceptor, alkynes could be utilized for facile
construction of complex functional molecules because of the
high activity of the in situ formed vinyl radical, which could
induce further cascade reactions.5,6 We assumed that a rapid
and efficient access to 7-membered cyclic sulfonamides might
be gained by direct intramolecular radical addition to the
aromatic ring of a vinyl radical intermediate. Considering that
only limited examples were reported for the synthesis of
dibenzazepines via an electrochemical7 or photocatalytic
protocol8 using this strategy, this tactic needs further
development to complement the current methodologies in
organic synthesis. As part of our interest in the construction of
7-membered rings,9 as well as the fact that the incorporation of
CF3 into organic molecules could obviously enhance the
lipophilicity, metabolic stability, and bioavailability,10 we report
a novel and facile approach to synthesize dioxodibenzothiaze-
pines via copper-catalyzed trifluoromethylation/cyclization of
terminal alkynes by radical relay. This strategy features low
catalyst loading, marvelous regio- and stereoselectivity, broad
scope, and mild conditions. The efficient incorporation of
trifluoromethyl group during this process enabled an applicable
synthetic tactic to construct CF3-containing intermediates for
further elaboration in organic synthesis.
We commenced our initial investigation with N-(2-
ethynylphenyl)-N-isopropyl-4-methylbenzenesulfonamide
(1a) used as the pilot substrate and Togni-II reagent as the
trifluoromethylating reagent in the presence of a catalytic
amount of CuI (2 mol %) and L1 (2 mol %) in DMF at 40 °C.
The desired product 2a was afforded in 44% yield after 24 h. A
general screening of multifarious copper salts using L1 as the
ligand was conducted subsequently (entries 1−5, Table 1; for
details, see the Supporting Information (SI)), which indicated
that CuI was still the optimal choice for this reaction with the
best yield. Normally used nitrogen-containing ligands with
various steric hindrance and electrical properties were next
screened (entries 6−10, Table 1; for details, see the SI). To
our delight, the electron-rich ligand 5,5′-dimethoxy-2,2′-
bipyridine (L5) could improve the yield of 2a to 65% (entry
9, Table 1). Solvents were then investigated and exerted a great
effect on this reaction; DMF remains the best choice (entries
11 and 12, Table 1; for details, see the SI, Table S4). To
increase the yield further, we attempted to add some additives
to the system. The addition of extra 1.0 equiv NaHCO3 as a
base into the reaction system resulted in a slight decrease in
the yield (entry 13), while the H2O could increase the yield of
2a to 74% (entry 14). We believe that the addition of water
significantly reduces the side reactions,11 thereby increasing the
yield of the product. As only 5% yield of 2a detected, AcOH
had been demonstrated not to be a good additive in this
catalytic system (entry 15). It is noteworthy that the prestirring
time of catalyst and ligand has a tremendous influence on the
reaction efficiency (Table S8, for details, see the SI).
Furthermore, prolonging the reaction time to 36 h could
furnish the desired product 2a with even higher yield (88%
isolated yield, entry 16, Table 1). It is worth mentioning that
only E-alkenes were observed in all these reactions.
Table 1. Optimization of Conditions
b
entry
[Cu]
CuI
L
solvent
yield (%)
1
L1
L1
L1
L1
L1
L2
L3
L4
L5
L6
L5
L5
L5
L5
L5
L5
L5
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
CH3CN
DCM
DMF
DMF
DMF
DMF
DMF
44
33
27
16
20
37
6
60
65
30
9
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
CuBr
CuCl
CuCl2
Cu(OAc)2
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
CuI
8
c
55
74
5
90 (88)
80
d
e
d
,
,
f
d
g
a
Reaction conditions: 1a (0.2 mmol, 1.0 equiv), Togni-II (0.3 mmol,
1.5 equiv), [Cu] (2 mol %), L (2 mol %), DMF (2.0 mL), 40 °C, 24
b
h, under N2. Yield was determined by 19F NMR using PhOCF3 as
c
internal standard, isolated yield in parentheses. NaHCO3 (1.0 equiv).
H2O (1.0 equiv). AcOH (1.0 equiv). 36 h. 48 h.
d
e
f
g
electrical properties of the substituents have a significant effect
on the reaction. A para-electron-donating group delivered
products in a slightly lower yield (2j), while para-electron-
withdrawing groups such as trifluoromethyl and cyano can be
transformed into the corresponding products in good yields
(2h,i). Intriguingly, meta-methyl-substituted substrate 1k
afforded 2k and 2k′ as cyclization products with 1:1 selectivity
in 76% yield in total. Ortho-substituted groups delivered
products in a slightly lower yield under the general method but
could be further increased to moderate yield by increasing the
catalyst loading to 3% and replacing the ligand with 6% DMAP
(2l,m). In particular, ortho-bromine-substituted substrate 1m
afforded the product 2m with an E/Z selectivity of 7:1, while o-
chlorine-substituted one gave the E product 2l only, which
indicated that the steric hindrance might play an important
role for the regiocontrol. Notably, the dimethyl-substituted
substrate 1n could be well tolerated with moderate yield (75%,
2n). The investigation of substituent (R1) effects of the
arylalkyne ring indicated that electron-donating groups such as
alkyl (2o, 2v) and methoxy (2s) groups, weak electron-
withdrawing groups such as fluoro (2p, 2w), chloro (2q, 2x),
and bromo (2r, 2y), and strong electron-withdrawing groups
such as esters (2t, 2z) and cyano (2u) could also be
compatible with our standard conditions. The absolute
configuration of 2p was confirmed by X-ray diffraction (for
With the optimized reaction conditions in hand, the scope of
this radical cyclization was then elucidated by the preparation
of a variety of dioxodibenzothiazepines (Scheme 2). A number
of arylalkynes 1 with para-, meta-, as well as ortho-substituted
groups (R3) on the aromatic ring attached to sulfonyl were
efficiently cyclized to furnish the desired products 2 with good
to excellent yields (2a−2n). It should be noted that the
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a,b
Further transformation of 2zf was carried out in a methanol/
H2O solution of sodium hydroxide at room temperature for 12
h (Scheme 3). As expected, the pivaloyl group cleaved reaction
of 2zf occurred to give deprotected amine 3zf in an excellent
yield of 92%.
Scheme 2. Substrate Scope
Scheme 3. Further Derivation
To gain further insight into the reaction mechanism, 2.0
equiv of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) was
subjected to the standard conditions shown in entry 16, Table
1. As a result, dioxodibenzothiazepine 2a could not be
detected, and the radical-trapping product 3a12 of the
trifluoromethyl radical by TEMPO was afforded in 62%
NMR yield (Scheme 4a). Furthermore, the addition of (1-
Scheme 4. Mechanistic Studies
a
Reaction conditions: 1 (0.2 mmol, 1.0 equiv), Togni-II (1.5 equiv),
cyclopropylvinyl)benzene, a normally used radical clock, to the
standard reactions furnished the known product 4a13 in 39%
NMR yield (Scheme 4b). Both observations clearly demon-
strated that this reaction initiated from the attack of in situ
generated trifluoromethyl radical to the terminal alkyne.
On the basis of the above observations and previous
reports,7,8 the plausible mechanism of this reaction is then
proposed (Scheme 5). Initially, CF3 radical is generated via a
single electron transfer (SET) process from Cu(I) species to
CuI (2 mol %), L5 (2 mol %), H2O (1.0 equiv), DMF (2.0 mL), 40
b
c
°C, 36 h, under N2. Isolated yield. CuI (3 mol %), DMAP (6 mol
d
%), H2O (1.0 equiv), DMF (2.0 mL), 40 °C, 36 h, under N2. E/Z =
e
7:1. Gram-scale synthesis.
details, see the SI). Similarly, electron-rich substrates could
afford the higher yields compared with the electron-deficient
substrates, which implied the electronic properties had an
impact on reaction efficiency. The protocol was also effective
for alkyne bearing both fluoro and chloro groups on the aryl
ring to furnish the desired product 2za with 63% yield.
Additionally, N-protecting groups were next evaluated. As an
analogue of drug molecules tianeptine and zepastine, N-
methyl-protected substrate was also compatible with this
transformation (2zb), albeit in a lower but still acceptable
yield. Other N-protecting groups such as cyclohexyl (2zc), Bz
(2zd), Boc (2ze), and Piv (2zf) were also amenable to this
catalytic system, which suggested the versatility of this method.
It should be mentioned that the ring-closure reaction occurs
preferentially on the aromatic ring attached to the sulfone
group rather than the one located on the Bz group (2zd). To
demonstrate the utility of the cascade cyclization, a gram-scale
reaction of 1zf with Togni-II reagent was carried out, and the
reaction gave rise to product 2zf with slightly lower yield (70%,
1.19 g).
Scheme 5. Proposed Mechanism
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Togni-II reagent, accompanied by the formation of the anion
species D and Cu(II) species. Then the CF3 radical is fleetly
trapped by the terminal alkyne 2a to afford the vinyl radical A,
followed by intramolecular addition of A for the formation of
the radical intermediate B. A single electron oxidant of the
radical intermediate B by Cu(II) species regenerates Cu(I)
species and affords the cation intermediate C, which furnishes
the desired product 2a along with E after the following
deprotonation under the promotion of the anion species D
(path a). Meanwhile, another possible pathway cannot be
excluded, in which the cation intermediate C may generate by
direct single electron transfer (SET) from the radical
intermediate B to Togni-II reagent with the generation of
the anion species D and CF3 radical to enter the next catalytic
cycle (path b).
Jing-Cheng Dai − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, China
Yan Li − Hefei National Laboratory for Physical Sciences at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China
Jie Sheng − Hefei National Laboratory for Physical Sciences at
the Microscale and Department of Chemistry, University of
Science and Technology of China, Hefei, Anhui 230026,
China
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00344
In conclusion, we have developed a novel, facile, and
efficient approach for the synthesis of dioxodibenzothiazepines
via copper-catalyzed trifluoromethylation/cyclization of arylal-
kynes utilizing Togni’s reagent as the trifluoromethyl source.
This method features low catalyst loading, marvelous regio-
and stereoselectivity, broad scope, and mild conditions. This
radical relay tactic offers a reliable manner for the
functionalization of arylalkynes and thus paves a potential
path for the facile synthesis of CF3-containing antidepressant
drugs. Further investigations on novel radical-involved cascade
cyclization of arylalkynes for efficient construction of complex
functional molecules in single step are still underway in our
laboratory.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We gratefully acknowledge the National Science Foundation of
China (21971228, 21772187) for financial support.
■
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CCDC 2005999 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
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data_request@ccdc.cam.ac.uk, or by contacting The Cam-
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Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Author
■
̂
P.; Mignani, G.; Fensterbank, L.; Lacote, E.; Malacria, M. Intra-
Xi-Sheng Wang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, China; orcid.org/0000-0003-2398-5669;
Email: xswang77@ustc.edu.cn
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Authors
Zi-Qi Zhang − Hefei National Laboratory for Physical
Sciences at the Microscale and Department of Chemistry,
University of Science and Technology of China, Hefei, Anhui
230026, China
Yi-Hao Xu − Hefei National Laboratory for Physical Sciences
at the Microscale and Department of Chemistry, University
of Science and Technology of China, Hefei, Anhui 230026,
China
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