Lewis-acid-mediated intramolecular trifluoromethylthiolation of alkenes with phenols: Access to SCF3-containing chromane and dihydrobenzofuran compounds

Article abstract of DOI:10.1021/acs.orglett.0c02744

A Lewis-acid-mediated intramolecular trifluoromethylthiolation of alkenes with phenols that can offer direct access to SCF3-containing chromane and dihydrobenzofuran compounds was disclosed for the first time. Numerous SCF3-containing chromanes were obtai

Full text of DOI:10.1021/acs.orglett.0c02744

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Letter
Lewis-Acid-Mediated Intramolecular Trifluoromethylthiolation of
Alkenes with Phenols: Access to SCF3‑Containing Chromane and
Dihydrobenzofuran Compounds
Xu-Feng Song, Tong-Mei Ding, Deng Zhu, Jie Huang, and Zhi-Min Chen*
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ABSTRACT: A Lewis-acid-mediated intramolecular trifluorome-
thylthiolation of alkenes with phenols that can offer direct access to
SCF3-containing chromane and dihydrobenzofuran compounds was
disclosed for the first time. Numerous SCF3-containing chromanes
were obtained in moderate to good yields using γ-substituted 2-
allyphenols as substrates. Meanwhile, various SCF3-containing
dihydrobenzofurans with oxa-quaternary centers were also delivered
in moderate to good yields using β-substituted 2-allyphenols as
substrates.
he chroman skeleton is widely present in bioactive
requires excellent control of the regioselectivity and diaster-
eoselectivity to solely afford the chroman product, which is
shown in Scheme 1b. The mixture of chroman and
dihydrobenzofuran would be obtained if the regioselectivity
was not well controlled. In addition, the relatively weak
nucleophilic capability of the phenolic hydroxyl group may be
a limiting factor, and the direct Friedel−Crafts reaction of the
phenol moiety is a nonignorable competing reaction. So, the
development of the electrophilic addition/cyclization of γ-
substituted 2-allyphenols to form 2,3-disubstituted chromans is
still challenging. The dihydrobenzofuran moiety is also an
important and usual scaffold for natural products and
pharmaceutical molecules (Scheme 1a).4 Consequently,
numerous synthetic methods for the preparation of dihy-
drobenzofuran compounds have been reported.5 Similarly,
only a few examples of the electrophilic addition/cyclization of
2-allyphenols have been documented.6 Therefore, the develop-
ment of methods for the straightforward and efficient synthesis
of chromans and dihydrobenzofurans is in high demand.
Because it shows high lipophilicity and strong electron-
withdrawing ability, introducing a SCF3 group into compounds
can make the compounds have unique chemical, biological,
and physical properties.7 Thus SCF3-containing compounds
broadly exist in pesticides, medicine, and functional materials.8
The development of methods for the efficient and rapid
synthesis of SCF3-containing compounds has attracted much
T
molecules, such as catechin and englitazone (Scheme
1a).1 Accordingly, various synthetic strategies have been
Scheme 1. Design for the Synthesis of SCF3-Containing
Chromane and Dihydrobenzofuran Compounds
developed.2 Among them, the electrophilic addition/cycliza-
tion of γ-substituted 2-allyphenols to form 2,3-disubstituted
chromans is a direct and efficient method. The method could
introduce a transformable and useful group at the three-
position of chroman and simultaneously construct two
continuous stereocenters (Scheme 1b). However, to our
surprise, the successful development of this type of method
remains rare.3 One of the difficulties may be that the reaction
Received: August 17, 2020
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© XXXX American Chemical Society
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attention, and various outstanding research works have been
disclosed.9 For example, the Billard and Shen groups have
independently explored some different useful SCF3 reagents
and achieved a number of fairly synthetic methods.10,11 The
Zhao group developed a variety of novel enantioselective
trifluoromethylthiolations of alkene-catalyzed chiral sulfide
compounds.12 However, trifluoromethylthiolations of alkenes
with phenols to afford SCF3-containing chromans and
dihydrobenzofurans have not been reported. Considering the
importance of chroman and dihydrobenzofuran units and
SCF3-containing compounds and combined with our interest
in fluorine and organosulfur chemistry,13 we hope to study the
trifluoromethylthiolations of γ-substituted 2-allyphenols to
afford 2,3-disubstituted chromans and β-substituted 2-
allyphenols to produce dihydrobenzofurans with oxa-quater-
nary centers (Scheme 1c). In this Letter, we report our
preliminary results.
the product in 60% yield (entry 4). Interestingly, only using
the acids containing chloride ions could produce the desired
product 3a. It could be explained that the more active
compound CF3SCl was formed in situ, which is the real SCF3
source in this system. (For details, see the SI.) After
determining TMSCl to be the acid, some other widely used
SCF3 reagents were tested, such as PhNHSCF3 developed by
Billard10 and (PhSO2)2NSCF3 developed by Shen.11d It was
found that no better result was observed in this system (entries
10 and 11). Next, we turned our attention to the screen
additive. Inspired by Zhao’s work,14 diphenyl selenide
(PhSePh) and diphenyl diselenide ((PhSe)2) were first
considered. However, both of the two additives resulted in
decreasing the yield (entries 12 and 13). To our delight, the
use of hexafluoroisopropanol (HFIP) as an additive can
obviously improve the conversion and then increase the
yield.15 After carefully screening the amount of HFIP, the best
result was obtained, producing the product 3a in 74% yield
when 10 equiv of hexafluoroisopropanol was used (entry 15).
It was found that the reaction hardly happened when using
only HFIP in the absence of TMSCl (entry 16). Thus we
surmised that the role of HFIP is as a cooperative activator.
With the optimized conditions in hand, the generality of this
tandem trifluoromethylthiolation/cyclization reaction was
evaluated with a wide range of 2-allyphenol derivatives
(Scheme 2). First, a number of substrates with different
Initially, (E)-cinnamylphenol (1a) was chosen as a model
substrate with N-trifluoromethylthiosaccharin 2a (Shen’s
reagent) as the SCF3 source to study the transformation for
the synthesis of chromanes (Table 1). The desired product 3a
Table 1. Screening of Reaction Conditions for the Synthesis
a
of SCF3-Containing Chromanes
Scheme 2. Substrate Scope of γ-Substituted 2-Allyphenols
a b
,
for the Synthesis of SCF3-Containing Chromanes
b
entry
acid (equiv)
SCF3 source
additive
yield (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
AcCl (3.0)
7 (3.0)
8 (3.0)
TMSCl (3.0)
BF3·Et2O (1.0)
HCl (3.0)
CF3CO2H (1.0)
CH3SO3H (1.0)
CF3SO3H (1.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
TMSCl (3.0)
2a
2a
2a
2a
2a
2a
2a
2a
2a
2b
2c
2a
2a
2a
2a
2a
46
58
53
60
34
26
c
c
PhSePh
(PhSe)2
55
41
68
74
c
c
d
d
HFIP
e
e
HFIP
e
e
HFIP
a
Reaction conditions: Unless otherwise noted, the reaction was
conducted with 1a (0.1 mmol), 2a (0.13 mmol), and acid (0.3 mmol)
b
in CH3CN (1 mL) at room temperature under Ar for 24 h. Isolated
c
d
yield. 0.1 equiv of additive was used. HFIP (1.0 equiv) was added.
e
HFIP (10 equiv) was added.
was obtained in 46% yield when acetyl chloride (AcCl) was
used as the Lewis acid in CH3CN (1 mL) at room temperature
(entry 1). It is worth mentioning that the reaction was
achieved with excellent regioselectivity and diastereoselectivity.
To improve the yield, a series of acids including the Lewis acid
and Brønsted acid were examined (entries 2−9). The use of
trimethylchlorosilane (TMSCl) gave the best result, affording
a
Reaction conditions: Unless otherwise noted, the reaction was
conducted with 1 (0.1 mmol), 2a (0.13 mmol), TMSCl (0.3 mmol),
and HFIP (1.0 mmol) in CH3CN (1 mL) at room temperature under
b
c
Ar. Isolated yield. 2.5 equiv of 2a was used.
B
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substituents at the four-position of phenol were investigated. In
general, the desired products were obtained in moderate yields
(3b−g). It was found that the electron-rich substituent can
improve the yield, whereas the electron-deficient substituent
decreases the yield (3g vs 3f). 2-Naphthol substrate 1h is also
suitable for the transformation, delivering the corresponding
product 3h in 67% yield. Next, a series of substrates with
different 1,2-disubstituted alkenes were subjected to the
reaction (3i−n). Similarly, the substrate with an electron-rich
alkene gave a higher yield than the electron-deficient alkene (3j
vs 3i). The position of the substituent at the phenyl group did
not obviously affect the yield (3j vs 3k). To our delight, the
substrate with thiophene 1l was well-tolerated, affording the
product 3l in 77% yield, but when the compound with furan
1m was used as the substrate, the desired cyclization product
was hardly observed, and the product 4m was mainly obtained
in 79% yield under standard reaction conditions. We
speculated that ditrifluoromethylthiolation/cyclization product
3m-1 could be obtained when the amount of 2a was further
increased. As expected, the product 3m-1 was produced in
42% yield using 2.5 equiv of 2a and 1m as the substrate. The
substrate with nonactivated alkyl alkene 1n was examined, and
the reaction still happened smoothly. It was found that SCF3-
containing chroman and dihydrobenzofuran were simulta-
neously obtained in 78% combined yield with an approximate
ratio of 1:1. Finally, normal alkyl alcohol 1o was tested, giving
single 6-endo product 3o in 50% yield. It should be noted that
the relative configuration of 3a was determined by X-ray
crystallography.
investigated, but the yield was not further improved.
Therefore, the conditions of entry 5 were chosen as the
optimal conditions.
Subsequently, the scope of the reaction was investigated
with a variety of β-substituted 2-allyphenols and 2-(2-
substituted ally)-1-naphthols. In general, the desired products
were obtained in moderate to good yields (Scheme 3).
Compared with 5h, β-substituted 2-allyphenols always gave
higher yields, except for 5c (5a−g).
Scheme 3. Substrate Scope of β-Substituted 2-Allyphenols
a
for the Synthesis of SCF3-Containing Dihydrobenzofurans
To solely synthesize SCF3-containing dihydrobenzofurans,
we considered that the use of β-substituted 2-allyphenol as a
substrate would be a better choice. Therefore, we turned our
attention to exploring the trifluoromethylthiolation/cyclization
of β-substituted 2-allyphenols (Table 2). It is a pity that the
Table 2. Screening of Reaction Conditions for the Synthesis
a
of SCF3-Containing Dihydrobenzofurans
a
Reaction conditions: Unless otherwise noted, the reaction was
conducted with 5 (0.1 mmol), 2a (0.13 mmol), 7 (0.3 mmol), and
HFIP (1.0 mmol) in CH3CN (1 mL) at room temperature under Ar.
Isolated yield. TMSCl was used instead of 7.
b
b
entry
acid (equiv)
SCF3 source
additive
HFIP
yield (%)
1
2
3
4
TMSCl (3.0)
AcCl (3.0)
7 (3.0)
8 (3.0)
7 (3.0)
2a
2a
2a
2a
2a
51
53
58
56
64
Both electron-rich groups at the four-positions of phenol
and alkene part gave higher yields than the electron-deficient
groups (6d vs 6c and 6g vs 6f). We found that 4-
methoxynaphthalen-1-ol 5j gave a 67% yield, whereas when
using 4-chloronaphthalen-1-ol 5i as the substrate, the yield was
decreased to 44%. To our delight, the product 6k was
produced in 70% yield with the use of electron-deficient
substrate 5k. It is interesting that the further Friedel−Crafts
product 6l-1 (34% yield), except for the desired product 6l
(46% yield), was also observed using electron-rich substrate 5l.
Unfortunately, product 6m was obtained in only 13% yield
when nonactivated 1,1-disubstituted alkene 5m was examined.
Likewise, alkene alcohol substrates 5n and 5o were also
conducted, affording the corresponding products in moderate
yields.
c
5
HFIP
a
Reaction conditions: Unless otherwise noted, the reaction was
conducted with 5h (0.1 mmol), 2a (0.13 mmol), and acid (3.0 equiv)
in CH3CN (1 mL) at room temperature under Ar for 6 h. Isolated
yield. HFIP (10 equiv) was added.
b
c
desired product 6h was obtained in only 51% yield under the
previously described standard conditions using 5h as the
substrate (entry 1). The yield was not satisfactory, and thus
screening a more suitable reaction condition for this type of
alkene substrate is necessary. As shown in Table 2, three Lewis
acids were first conducted based on the previously described
results, and the product was afforded in 58% yield when
ethyloxalyl chloride 7 was used as an acid (entry 3). Adding
HFIP can also promote the reaction, and the yield was
increased to 64%. Other conditions have also been
To evaluate the practicability of these two trifluoromethylth-
iolation/cyclization reactions, 1 mmol scale transformations of
1j and 5f were carried out, respectively. To our delight,
product 3j was obtained in 83% yield, and 6f was produced in
C
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Letter
64% yield (Scheme 4). The yields of the two reactions were
basically maintained. Furthermore, a 1 g scale reaction of 1j
was also performed, delivering product 3j in 83% yield.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
■
sı
https://pubs.acs.org/doi/10.1021/acs.orglett.0c02744.
Scheme 4. 1 mmol Scale Reactions
Experimental procedures, characterizations and analyt-
ical data of products, and NMR spectra (PDF)
Accession Codes
CCDC 2014660 contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
via www.ccdc.cam.ac.uk/data_request/cif, or by emailing
data_request@ccdc.cam.ac.uk, or by contacting The Cam-
bridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
1
AUTHOR INFORMATION
Corresponding Author
To gain further insight into this transformation, some H
■
NMR and 19F NMR spectroscopy studies were performed.
(For details, see the SI.) On the basis of previous works and
our results, a possible mechanism for the intramolecular
trifluoromethylthiolation of 2-allyphenol is proposed in
Scheme 5. The active compound CF3SCl is first formed in
Zhi-Min Chen − School of Chemistry and Chemical
Engineering, Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs and Frontiers Science Center for
Transformative Molecules, Shanghai Jiao Tong University,
Shanghai 200240, P. R. China; orcid.org/0000-0002-
6988-8955; Email: chenzhimin221@sjtu.edu.cn
Scheme 5. Proposed Mechanism
Authors
Xu-Feng Song − School of Chemistry and Chemical Engineering,
Shanghai Key Laboratory for Molecular Engineering of Chiral
Drugs and Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
P. R. China
Tong-Mei Ding − School of Chemistry and Chemical
Engineering, Shanghai Key Laboratory for Molecular
Engineering of Chiral Drugs and Frontiers Science Center for
Transformative Molecules, Shanghai Jiao Tong University,
Shanghai 200240, P. R. China
the presence of Shen’s reagent 2a, HFIP, and TMSCl. (See the
19F NMR data in the SI.) HFIP may act as an activator via the
hydrogen-bonding interaction and provide a proton for the
1
formation of saccharin. (See the H NMR data in the SI.)
Deng Zhu − School of Chemistry and Chemical Engineering,
Shanghai Key Laboratory for Molecular Engineering of Chiral
Drugs and Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
P. R. China
Jie Huang − School of Chemistry and Chemical Engineering,
Shanghai Key Laboratory for Molecular Engineering of Chiral
Drugs and Frontiers Science Center for Transformative
Molecules, Shanghai Jiao Tong University, Shanghai 200240,
P. R. China
Additionally, TMSCl also can directly activate Shen’s reagent
2a to form CF3SCl. Next, compound CF3SCl undergoes
electrophilic addition to (E)-cinnamylphenol 1a, generating
CF3-substituted thiiranium ion intermediate 9a, which is
attacked by a phenolic hydroxyl group, and the desired 6-
endo product 3a will form after further deprotonation. The
collaborative process determines the excellent diastereoselec-
tivity of this reaction. When the R2 group is an aromatic ring,
the substrates have a strong electronic bias for thiiranium ion
opening, which could account for the excellent regioselectivity.
By contrast, the substrate with an alkyl group is unbiased, so
the regioselectivity of 1n is poor. For 1,1-disubstituted
(whatever substituent) alkenes, the regioselectivity also results
from the distinct electronic bias for the thiiranium ion opening.
In summary, we successfully developed a tandem trifluor-
omethylthiolation/cyclization of alkenes with phenols, which
could provide a direct and modular approach to SCF3-
containing chromane and dihydrobenzofuran compounds for
the first time. These two transformations feature simple and
mild conditions and broad substrate toleration and are
transition-metal-free. A variety of chromanes and dihydroben-
zofurans were synthesized in moderate to good yields. We are
investigating the catalytic enantioselective manner of this type
of reaction.
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c02744
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We acknowledge the NSFC (nos. 21871178, 21702135) and
the STCSM (19JC1430100) for the financial support. This
research was also supported by The Program for Professor of
Special Appointment (Eastern Scholar) at Shanghai Institu-
tions of Higher Learning.
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