Ir(III)-Catalyzed mono-olefination of Aryl C-H Bonds Using -SCF3 as a Weak directing group

Article abstract of DOI:10.1021/acs.orglett.9b03125

The trifluoromethylthionyl group (-SCF₃) is an efficient weak directing group for Ir(III)-catalyzed aryl C-H olefination. Various trifluoromethylthioethers provide high levels of mono-olefination products in good to excellent yields under mild conditions with a 2,2′-bipyridine ligand or AgBF₄ as an additive. Mechanistic studies indicate the C-H cleavage is the rate-determining step. The directing group ability of the -SCF₃ group is benchmarked against several other weak directing groups by competition experiments under Ir(III)-catalyzed conditions.

Full text of DOI:10.1021/acs.orglett.9b03125

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Ir(III)-Catalyzed Mono-Olefination of Aryl C−H Bonds Using −SCF3 as
a Weak Directing Group
Rui-Peng Bao,† Xian Chen,‡ Chen Li,*,‡ and Dong-Hui Wang*,†
†CAS Key Laboratory of Synthetic and Self-Assembly Chemistry for Organic Functional Molecules, Center for Excellence in
Molecular Synthesis, University of Chinese Academy of Sciences, Shanghai Institute of Organic Chemistry, CAS. 345 Lingling Road,
Shanghai 200032, China
‡School of Biotechnology and Health Sciences, Wuyi University, 22 Dongcheng Vill., Jiangmen, Guangdong 529020, China
S
* Supporting Information
ABSTRACT: The trifluoromethylthionyl group (−SCF3) is
an efficient weak directing group for Ir(III)-catalyzed aryl C−
H olefination. Various trifluoromethylthioethers provide high
levels of mono-olefination products in good to excellent yields
under mild conditions with a 2,2′-bipyridine ligand or AgBF4
as an additive. Mechanistic studies indicate the C−H cleavage
is the rate-determining step. The directing group ability of the
−SCF3 group is benchmarked against several other weak
directing groups by competition experiments under Ir(III)-catalyzed conditions.
ate-stage modification of organic compounds that delivers
Lmore diverse products has become a powerful tool in the
total synthesis of natural products, the discovery of bioactive
molecules, and peptide research. One potential method to
achieve this goal is C−H functionalization.1 To date, the
majority C−H bond activation reactions use N- or O-atom-
based directing groups, including pyridine,2 oxazoline,3 amine,4
imine,5 carboxylic acid,6 alcohol,7 and cyanide.8 Molecules that
contain chemically less reactive but nevertheless valuable
functional groups, such as the trifluoromethylthio group
(−SCF3), are rarely studied. Herein, we report an Ir-catalyzed
−SCF3-directed monoalkenylation for aryl C−H bonds.
The trifluoromethylthio (−SCF3) moiety is a chemically
inert building block that is dimensionally analogous to the
methoxy group. The introduction of −SCF3 onto bioactive
molecules can dramatically improve their lipophilicity, reduce
electron density, and enhance cell-membrane permeability.9 As
such, in the past decade, academic, pharmaceutical, and
agrochemical industries have demonstrated escalating interest
in installing −SCF3 groups onto existing organic molecules,
and many methods have been developed.10 However, there
remains a high demand for practical new methods to prepare
−SCF3-containing group that proceed under mild conditions,
employ common reactants, involve short synthetic routes, and
exhibit wide functional group tolerance. In parallel, achieving
controllable positional selectivity during transformations is also
a pertinent challenge.
have revealed that thiocarbonyls,12 sulfoxides,13 and alkyl or
aryl thioethers14−17 can direct C−H arylation, alkenylation,
alkylation, and cyclization with Pd-, Rh-, and Ru-catalysts
(Figure 1a−d). Herein, we report that −SCF3 is an efficient
weak directing group for mono-C−H olefination with the
(Cp*IrCl2)2 catalyst under mild conditions. Particularly, we
found that the use of 2,2′-bipyridine as ligand for electron-rich
To this end, we envisioned that −SCF3 could be installed in
the early stages of a synthetic sequence and then be used as a
directing group for the subsequent late-stage C−H function-
alization. Though it is traditionally believed that the sulfur (S)
atom will poison transition-metal catalysts because of its
inherently strong coordinating ability,11 recent breakthroughs
Figure 1. Sulfur-directed C−H functionalization.
Received: September 3, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b03125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Table 1. Optimization of Reaction Conditions
b
entry
catalyst (mol %)
oxidant
base
additive
yield
c
1
2
3
4
5
6
7
8
9
Pd(OAc)2 (10 mol %)
Pd(OAc)2 (10 mol %)
Pd(OAc)2 (10 mol %)
Pd(OAc)2 (10 mol %)
Pd(OAc)2 (10 mol %)
[RuC12(p-cymene)]2 (10 mol %)
[Cp*RhC12]2 (10 mol %)
[Cp*IrC12]2 (5 mol %)
[Cp*IrC12]2 (5 mol %)
[Cp*IrC12]2 (5 mol %)
O2
O2
KHCO3
KHCO3
KHCO3
Na2SO4
--
--
--
--
--
--
Ac-Val-OH (20 mol %)
Ac-Val-OH (20 mol %)
Ac-Val-OH (20 mol %)
Ac-Val-OH (20 mol %)
--
AgSbF6 (40 mol %)
AgSbF6 (40 mol %)
--
(10%)
15%
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
55%(50%)
76%(71%)
(72%)
10%
26%
(34% mono + 65% di)
(85%)
2,2′-bipyridine (10 mol %)
AgBF4 (20 mol %)
d
10
(88%)
a
b
Reaction conditions: 1a (0.1 mmol), 2a (0.2 mmol), HFIP (1 mL), base (0.2 mmol). Yield is relative to internal standard Ph3CH as measured by
c
d
1H NMR; isolated yields are reported in parentheses. tert-Amyl alcohol was solvent. 4-(Trifluoromethoxy)benzyl trifluoromethylsulfane was the
starting material.
substrates and AgBF4 as an additive for electron-deficient
substrates ensured high-yielding mono-C−H alkenylation
(Figure 1).
monoalkenylation products in high yields. On the other hand,
AgBF4 was found to be a good additive for electron-deficient
substrates, and under these conditions the reaction provided
the desired mono-olefinated products in satisfying yields (entry
10).
We first probed the directive ability of the −SCF3 group in
aryl C−H functionalization, namely, the alkenylation between
benzyl trifluoromethylthio ether (1a) and ethyl acrylate (2a)
(Table 1). When Pd(OAc)2 was used as the catalyst in the
presence of Ac-Val-OH, KHCO3, and O2 in tert-amyl alcohol,
the desired alkenylation product (3a) was obtained in 10%
yield (entry 1). After carefully optimizing the reaction
conditions, 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) was
found to be an optimal solvent, giving 3a in 15% yield
without detectable side reactions or decomposition of 1a
(entry 2). Cu(OAc)2 proved to be a superior oxidant over
others that were tested (entry 3). The yield of 3a increased to
72% when the reaction was conducted at 80 °C for 12 h in the
absence of amino acid or base (entries 4 and 5). However,
ultimately only a few electron-rich trifluoromethylthio
substrates (1) were found to be compatible under these Pd-
catalyzed conditions; most trifluoromethylthio ethers gave low
yields or remained untouched under the standard protocol.
(For details regarding optimization of reaction conditions and
substrate scope under Pd-catalysis, see the SI). We
hypothesized that though alkyl or aryl thioethers have been
demonstrated to be efficient directing groups in Pd-catalyzed
C−H functionalization,14−16 the innate properties of the
−SCF3 group (particularly its electron-withdrawing character)
may dramatically attenuate the reactivity of the Pd catalyst in
C−H olefination. Inspired by the work of Chang,18 we next
examined the reactivity of other transition metals in this
transformation. Indeed, we found that under the similar
reaction conditions use of catalytic [RuCl2(p-cymene)]2
provided 10% yield of the desired product (entry 6), and use
of catalytic [Cp*RhCl2]2 afforded 26% yield of the desired
product (entry 7). When [Cp*IrCl2]2 was used as the catalyst,
the reaction gave quantitative conversion of starting material
1a, delivering 34% yield of monoalkenylation product 3a,
together with 65% yield of 2,6-dialkenylation product 3aa
(entry 8). In order to control the Ir-catalyst’s activity and
achieve mono-C−H selectivity in the transformation, various
ancillary ligands were tested.19 After extensive screening, we
found that 2,2′-bipyridine was a good ligand for electron-rich
substrates, and under these conditions the reaction provided
With these optimized conditions, we examined the
trifluoromethylthio ether substrate scope with ethyl acrylate
(Scheme 1). For trifluoromethylthio ethers with electron-rich
substituents, 2,2′-bipyridine was employed as the ligand in
order to reduce the rate of a second C−H olefination event,
thereby maintaining high mono-selectivity. Various electron-
rich −SCF3 ethers provided mono-olefinated products in good
to excellent yields (3a−3g). Sterically bulky substituents on
the aryl ring are well tolerated. For example, aryl rings
containing methyl groups at the ortho-, meta-, and para-
positions readily provided the desired products in 80−98%
yields (3b−3d). Phenyl, tert-butyl, and methoxyl substituents
also gave high yields of the corresponding mono-olefinated
products (3e−3g). A substrate containing 3,5-dimethyl
substitution offered moderate yield of the desired product
(3h) along with unreacted starting materials. The reaction of
2-naphthylmethyl trifluoromethyl sulfane takes place selec-
tively at the β-position and provides 91% yield of 3i. Notably,
when increasing the amounts of 2a to 4 equiv and of
Cu(OAc)2 to 2.2 equiv, the dialkenylation product is obtained
in 80% yield (3aa).
For substrates containing electron-deficient substituents, the
AgBF4 additive was found to increase Ir-catalyst reactivity.
Substrates containing fluoride and bromide reacted smoothly
to provide the desired mono-olefinated products in 78−82%
yields (3j and 3k). The iodide substituent was also compatible
with the reaction conditions, offering moderate yield of the
desired product (3l). These halide substituents provide an
extra opportunity for further synthetic elaboration. Substrates
with −SCF3 and −OCF3 substituents delivered the mono-
olefinated products in 72% and 79% yields, respectively (3m
and 4n). A nitro substituent was also tolerated, albeit in
moderate yield (3o). Ester groups were compatible in the
reaction, affording the desired products in 77−87% yields (3p,
3q).
A series of alkene coupling partners were examined with 4-
tert-butylbenzyl trifluoromethyl sulfane (1f) (Scheme 2).
Acrylates were found to be a good coupling partner for this
B
DOI: 10.1021/acs.orglett.9b03125
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
acrylate was used as the starting material, the corresponding
cinnamic acid product 4f was isolated in 85% yield after
treating the crude reaction mixture with aq. HCl prior to
purification. Other alkenes, such as phenyl vinyl sulfone, ethyl
vinyl ketone, and vinyl diethylphosphate, reacted smoothly
with 1f to provide the desired mono-olefination products in
66−77% yields (4g−4i). These conditions were also found to
be compatible with styrene, and moderate yields of the
coupling products were obtained (4j and 4k). However,
acrylonitrile gave only a trace amount of the desired product
(4l).
Scheme 1. Substrate Scope for Trifluoromethylsulfanes
In order to understand the mechanistic details of this
transformation, we performed kinetic isotope effect experi-
ments (KIEs). When benzyl trifluoromethyl sulfane (1a) and
its deuterated analogue (1a-d5) were subjected to the reaction
conditions in the same pot and reacted for 2 h (Scheme 3),
Scheme 3. Kinetic Isotopic Experiment
a
kH/kD = 3.3 was measured. When monodeuterated substrate
1a-d1 was used as the starting material, we were able to
measure kH/kD = 4.6. These two experiments indicate that the
C−H cleaving step involves the rate-determining step.
Reaction conditions: 1 (0.3 mmol), 2a (0.6 mmol), (Cp*IrCl2)2 (5
b
mol %), Cu(OAc)2 (1.2 equiv), HFIP (3 mL), 80 °C, 12 h. 10 mol
c
% of 2,2′-bipyridine was added for electron-rich substrates. 10 mol %
of AgBF4 was added for electron-deficient substrates.
This Ir3+/Cu2+/HFIP catalytic system was found to be
generally applicable for aryl C−H olefinations directed by
several other weakly coordinating directing groups. For
example, when acetophenone (5), benzamide (6), benzoic
acid (7), and benzyl phenyl thioether (8) were subjected to the
standard reaction conditions (i.e., in the presence of
[Cp*IrCl2]2 (5 mol %), ethyl acrylate (2.0 equiv), and
Cu(OAc)2 (1.2 equiv) in HFIP (0.1 M) at 80 °C for 12 h), the
starting materials were fully converted to the corresponding
C−H olefination products. Excellent yields were obtained for
mono-alkenylation or di-alkenylation (Scheme 4). These
results make this protocol a perfect platform to evaluate the
relative effectiveness of these different directing groups in Ir-
catalyzed aryl C−H olefination. Notably, empirical head-to-
head comparison of directing groups containing different
coordinating atoms/moieties has rarely been studied.20
a
Scheme 2. Alkene Scope
To this end, we used our optimal reaction conditions as a
platform to conduct a series of binary competition experiments
between the two reactants with the acrylate as the limiting
reagent. As an illustrative example, we found that when a
mixture of 0.3 mmol of benzyl phenyl sulfide (8) and 0.3 mmol
of benzoic acid (7) was allowed to competitively react with
0.15 mmol of ethyl acrylate (2a), a single product, 8a, was
obtained in 47% yield (based on the acrylate) (Scheme 5a),
and this result indicated that the phenyl sulfide was a more
efficient directing group than the carboxylic acid under our
optimal reaction conditions. Similarly, when an equimolar
mixture of benzoic acid (7) and benzamide (6) was
competitively reacted with a limited amount of acrylate (2a),
a
Reaction conditions: 1g (0.3 mmol), 2 (0.6 mmol), (Cp*IrCl2)2 (5
b
mol %), Cu(OAc)2 (1.2 equiv), HFIP (3 mL), 80 °C, 12 h. 4.0 equiv
of 2 was added, and 2,2′-bipyridine was removed.
transformation, providing mono-olefinated products in 67−
85% yields (4a−4f). Various substituents on the acrylate were
tolerated, including an ether (4a, 4b), a benzyl group (4c), a
cyano group (4d), and a free alcohol (4e). When tert-butyl
C
DOI: 10.1021/acs.orglett.9b03125
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Organic Letters
Letter
groups under our optimal Ir-catalyzed aryl C−H olefination
conditions: phenyl sulfide (8) possessed the strongest ability in
terms of products providing, followed by benzoic acid (7),
which has been widely studied as a weakly coordinating
directing group, followed by benzamide (6), trifluoromethyl
thioether (1a), and acetophenone (5), the latter of which is the
weakest one among these directing groups.
Scheme 4. Ir(III)-Catalyzed Olefinations with Various
Directing Groups
In summary, the trifluoromethylthio group (−SCF3) is
demonstrated to be an efficient weakly coordinating directing
group in Ir(III)-catalyzed aryl mono-C−H alkenylation. The
catalytic activity of substrates with different electronic
properties can be controlled by employing 2,2′-dipyridine
ligand or AgBF4 as additive. A wide range of molecules with
better functional group diversity are prepared in good to
excellent yields. Mechanistic investigation reveals that C−H
cleavage is the rate-determining step. We also use these
general reaction conditions as a platform to examine several
classic weakly coordinating directing groups to benchmark
their relative effectiveness in Ir-catalyzed aryl C−H olefination
reactions.
Scheme 5. Comparison of Directing Ability under Optimal
Reaction Conditions
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b03125.
Experimental procedures and spectral data for new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*D.-H. Wang: dhwang@sioc.ac.cn.
*C. Li: wyuchemlc@126.com.
ORCID
Dong-Hui Wang: 0000-0002-4318-5450
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We gratefully acknowledge support from the National Key
R&D Program of China (2016YFA0202900), the Strategic
Priority Research Program of the Chinese Academy of
Sciences (XDB20000000), and the CNSF 21871286. X.C.
thanks the Foundation from Guangdong Education Depart-
ment (No. 2016KCXTD005 and 2017KSY010).
the major products were mono-olefination/cyclization prod-
ucts 7a and 7a′, which add up to 18% yield, together with
diolefination/cyclization production of 7b in 4% yield;
benzamide-derived product 6a was obtained in only in 3%
yield (Scheme 5b). These results indicated that benzoic acid
was a more efficient directing group than benzamide under
these competing conditions (about 7-fold faster, if applicable).
In the competitive reaction of benzamide (6) with
trifluoromethylthio ether (1a), we isolated 15% of 6b and
10% of 6a, together with 12% of 3a (Scheme 5c), which
indicated that benzamide was a more efficient directing group
than trifluoromethyl thioether under our optimal reaction
conditions (about twice as fast, if applicable). The competing
reaction between trifluoromethyl thioether (1a) and aceto-
phenone (5) provided 3a in 65% yield and 5a in 35% yield,
which showed that trifluoromethyl thioether was a more
efficient-directing group than acetophenone under these
conditions (Scheme 5d). (For more competition details
between these reactants, see the SI.) Taking all these results
together, we concluded the capability order of these directing
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